Dolastatin 15 derivatives

ABSTRACT

Compounds of the present invention include cell growth inhibitors which are peptides of Formula I  
     A-B-D-E-F-G (I)  
     and acid salts thereof, wherein A, D, and E are α-amino acid residues, B is an α-amino acid residue or an α-hydroxy acid residue, F is an aminobenzoic acid residue or an aminocycloalkanecarboxylic acid residue, and G is a monovalent radical, such as, for example, a hydrogen atom, an amino group, an alkyl group, an alkylene alkyl ether, an alkylene alkyl thioether, an alkylene aldehyde, an alkylene amide, a β-hydroxylamino group, a hydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group, an oximato group, an alkylene aryl group, an alkylene ester, an alkylene sultoxide or an alkylene sulfone. Another aspect of the present invention includes pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier. An additional embodiment of the present invention is a method for treating cancer in a mammal, such as a human, comprising administering to the mammal an effective amount of a compound of Formula I in a pharmaceutically acceptable composition.

RELATED APPLICATION(S)

[0001] This application is a continuation of International Application No. PCT/US99/14099, which designated the United States and was filed on Jun. 23, 1999, published in English, which is a continuation of, and claims priority to, Ser. No. 09/112,249, filed Jul. 8, 1998, the teachings of which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

[0002] A number of short peptides with significant activity as inhibitors of cell growth have been isolated from the Indian Ocean sea hare Dolabella auricularia (Bai, et al., Biochem. Pharmacology 40: 1859-1864 (1990); Beckwith et al., J. Natl. Cancer Inst. 85: 483-488 (1993) and references cited therein). These include Dolastatins 1-10 (U.S. Pat. No. 4,816,444, issued to Pettit et al.) and Dolastatin-15 (European Patent Application No. 398558). Dolastatin 15, for example, markedly inhibits the growth of the National Cancer Institute's P388 lymphocytic leukemia (PS system) cell line, a strong predictor of efficacy against various types of human malignancies.

[0003] The exceedingly small amounts of the various Dolastatin peptides present in Dolabella auricularia (about 1 mg each per 100 kg sea hare) and the consequent difficulties in purifying amounts sufficient for evaluation and use, have motivated efforts toward the synthesis of these compounds (Roux et al., Tetrahedron 50: 5345-5360 (1994); Shioiri et al., Tetrahedron 49: 1913-24 (1993); Patino et al., Tetrahedron 48: 4115-4122 (1992) and references cited therein). Synthetic Dolastatin 15, however, suffers from drawbacks which include poor solubility in aqueous systems and the need for expensive starting materials for its synthesis. These, in turn, have led to the synthesis and evaluation of structurally modified Dolastatin 15 derivatives (see, for example, Bioorg. Med. Chem. Lett. 4: 1947-50 (1994); WO 93 03054; JP-A-06234790).

[0004] However, there is a need for synthetic compounds with the biological activity of Dolastatin 15 which have useful aqueous solubility and can be produced efficiently and economically.

SUMMARY OF THE INVENTION

[0005] Compounds of the present invention include cell growth inhibitors which are peptides of Formula I

A-B-D-E-F-G (I)

[0006] and acid salts thereof, wherein A, D, and E are α-amino acid residues, B is an α-amino acid residue, F is an aminobenzoic acid residue or an aminocycloalkanecarboxylic acid residue, and G is a monovalent radical, such as, for example, a hydrogen atom, an amino group, an alkyl group, an alkylene alkyl ether, an alkylene alkyl thioether, an alkylene aldehyde, an alkylene amide, a β-hydroxylamino group, a hydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group, an oximato group, an alkylene aryl group, an alkylene ester, an alkylene sulfoxide or an alkylene sulfone.

[0007] Another aspect of the present invention includes pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.

[0008] An additional embodiment of the present invention is a method for treating cancer in a mammal, such as a human, comprising administering to the mammal an effective amount of a compound of Formula I in a pharmaceutically acceptable composition.

[0009] The present invention provides compounds with antineoplastic activity as well as increased metabolic stability relative to Dolastatin 15.

DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention relates to peptides having antineoplastic activity. It also includes pharmaceutical compositions comprising these compounds and methods for treating cancer in a mammal, including a human, by administration of these compositions to the mammal.

[0011] The invention is based on the discovery that Dolastatin 15, a peptide isolated from the sea hare Dolabella auricularia, is a potent inhibitor of cell growth. This compound, however, is present in trace quantities in the sea hare, and is, thus, difficult to isolate and expensive to synthesize and suffers from poor aqueous solubility. As shown herein, however, Dolastatin 15 can serve as a starting point for the development of compounds which overcome these disadvantages while retaining antineoplastic activity or exhibiting greater antineoplastic activity than the natural product. Applicants have discovered that certain structural modifications of Dolastatin 15 provide compounds with a surprisingly improved therapeutic potential for the treatment of neoplastic diseases as compared to Dolastatins-10 and -15. The Dolastatin-15 derivatives exhibit activity even in multiple drug-resistant tumor systems and an unpredicted high solubility in aqueous solvents. Furthermore, the compounds of the present invention can be conveniently synthesized, as described below in detail.

[0012] For the purposes of the present invention, the term “monovalent radical” is intended to mean an electrically neutral molecular fragment capable of forming one covalent bond with a second neutral molecular fragment. Monovalent radicals include the hydrogen atom, alkyl groups, such as methyl, ethyl and propyl groups, halogen atoms, such as fluorine, chlorine and bromine atoms, aryl groups, such as phenyl and naphthyl groups, and alkoxy groups, such as methoxy and ethoxy groups. Two monovalent radicals on adjacent sigma-bonded atoms can also together form a pi bond between the adjacent atoms. Two monovalent radicals may also be linked together, for example, by a polymethylene unit, to form a cyclic structure. For example, in the unit —N(R)R′, R and R′ are each a monovalent radical, and can, together with the nitrogen atom, form a heterocyclic ring. In addition, two monovalent radicals bonded to the same atom can also together form a divalent radical, such as an alkylidene group, for example, a propylidene group, or an oxygen atom.

[0013] For the purposes of the present invention, the term “residue” refers to the molecular fragment remaining after the removal of the elements of a water molecule (one oxygen atom, two hydrogen atoms) from a molecule, such as an amino acid or a hydroxy acid.

[0014] For the purposes of the present invention the term “normal alkyl” refers to an unbranched, or straight chain, alkyl group, for example, normal propyl (n-propyl, —CH₂CH₂CH₃).

[0015] The compounds of the present invention can be represented by Formula I,

A-B-D-E-F-G (I),

[0016] wherein A, D and E are α-amino acid residues; B is an α -amino acid residue or an α-hydroxy acid residue; F is an aminobenzoic acid residue, or an aminocycloalkanecarboxylic acid residue, such as an aminocyclobutanecarboxylic acid residue, an aminocylopentanecarboxylic acid residue, or an aminocyclohexanecarboxylic acid residue; and G is a monovalent radical.

[0017] The peptides of Formula I are generally composed of L-amino acids but they can contain one or more D-amino acids. They can also be present as salts with physiologically-compatible acids, including hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.

[0018] The following is a description of the present invention, including a detailed description of individual components and of methods of using the claimed compounds.

Compounds of the Present Invention

[0019] Identity of A

[0020] In one embodiment, A is an amino acid derivative of Formula II_(a),

[0021] where n_(a) is an integer, preferably 0, 1, 2, or 3. R_(a) is a monovalent radical, such as a hydrogen atom or a C₁-C₃-alkyl group which can be normal, branched or cyclic and can be substituted by one or more, preferably 1 to about 3, fluorine atoms; suitable examples include methyl, ethyl, isopropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl, 1-fluoromethyl-2-fluoroethyl or cyclopropyl; methyl, ethyl or isopropyl are preferred;

[0022] In this embodiment, R¹ _(a) is a monovalent radical, such as a hydrogen atom or a methyl, ethyl, propyl or phenyl group. The phenyl group can be substituted; suitable substituents include one or more halogen atoms, with fluorine, chlorine and bromine being preferred, C₁-C₄-alkyl groups, methoxy, ethoxy, trifluoromethyl or nitro groups.

[0023] R² _(a), R³ _(a), R⁴ _(a) and R⁵ _(a) are each, independently, a monovalent radical, such as a hydrogen atom or a methyl group. R_(a) and R¹ _(a) together can also form a propylene bridge.

[0024] In another embodiment, A is an amino acid derivative of Formula III_(a),

[0025] where R_(a) has the meaning stated for Formula II_(a), R¹ _(a) is a monovalent radical, for example, a hydrogen atom or a lower alkyl group, preferably a methyl, ethyl or propyl group.

[0026] In this embodiment, R⁶ _(a) is a monovalent radical, such as a hydrogen atom, a normal or branched C₁-C₈-alkyl group, which can he substituted by one or more halogen, preferably fluorine, atoms, or a C₃-C₈-cycloalkyl or C₃-C₈-cycloalkyl-C ₁-C₄-alkyl group, a C₁-C₄-oxoalkyl group such as a methoxymethyl, 1-methoxyethyl or 1,1-dimethylhydroxymethyl group, a C₂-C₅ alkenyl group, such as a vinyl or 1-methylvinyl group, or a substituted or unsubstituted phenyl group. Suitable phenyl substituents include one or more halogen atoms, preferably fluorine, chlorine or bromine atoms, and alkyl, methoxy, ethoxy, trifluoromethyl, or nitro groups. R⁷ _(a) is a monovalent radical, preferably a methyl group or an ethyl group.

[0027] In another embodiment, A is an amino acid residue of Formula IV_(a),

[0028] where m_(a) is an integer, preferably 1 or 2. R_(a) and R⁷ _(a) have the meanings stated for R_(a) and R⁷ ^(a) in Formula III_(a).

[0029] In another embodiment, A is an amino acid residue of Formula V_(a),

[0030] where R_(a) and R⁷ _(a) have the meanings stated for R_(a) and R⁷ ^(a) in Formula III_(a).

[0031] In a further embodiment, A is a substituted proline derivative of Formula VI_(a),

[0032] where R_(a) and R¹ _(a) have the meanings stated for R_(a) and R¹ _(a) in Formula II_(a), and X_(a) is a monovalent radical, preferably a hydroxyl, methoxy or ethoxy group or a fluorine atom.

[0033] In another embodiment, A is a thiaprolyl derivative of Formula VII_(a),

[0034] where R_(a), R¹ _(a), R² _(a), R³ _(a), R⁴ _(a) and R⁵ _(a) have the meanings stated for these variables in Formula II_(a).

[0035] In another embodiment, A is a 1,3-dihydroisoindole derivative of Formula VIII_(a),

[0036] where R_(a) has the meaning stated for R_(a) in Formula II_(a).

[0037] In another embodiment, A is a 2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivative of Formula IX_(a),

[0038] where Z_(a) is a single or double bond and R_(a) has the meaning stated for this variable in Formula II_(a). The 3-carbonyl substituent can have either the exo or endo orientation.

[0039] Identity of B

[0040] B is a valyl, isoleucyl, allo-isoleucyl, norvalyl, 2-tert-butylglycyl or 2-ethylglycyl residue. B can also be a carboxylic acid derivative of Formula IIb,

[0041] wherein R¹ _(b) and R² _(b) are each a monovalent radical. R¹ _(b) is, preferably, a hydrogen atom and R² _(b) is, for example, a cyclopropyl group, a normal or branched butyl, preferably tertiary-butyl, group, a methoxymethyl group, a 1-methoxyethyl group or a 1-methylvinyl group. Additionally, R¹ _(b) and R² _(b) together can be an isopropylidene group.

[0042] Identity of D

[0043] D is an N-alkylvalyl, N-alkyl-2-ethylglycyl, N-alkyl-2-tert-butylglycyl, N-alkyl-norleucyl, N-alkyl-isoleucyl, N-alkyl-allo-isoleucyl or N-alkyl-norvalyl residue, where the alkyl group is preferably methyl or ethyl.

[0044] In another embodiment, D is an α-amino carboxylic acid derivative of Formula II_(d),

[0045] where R_(d) has the meaning stated for R_(a) in Formula III_(a), R¹ _(d) is a monovalent radical, preferably a hydrogen atom, and R² is a monovalent radical such as a cyclopropyl group, a methoxymethyl group, a 1-methoxyethyl group or a 1-methylvinyl group. Additionally, R¹ _(d) and R² _(d) together can form an isopropylidene group.

[0046] Alternatively, D can be a proline derivative of Formula III_(d),

[0047] where n_(d) is an integer, for example, 1 or 2. and R³ _(d) has the meaning stated for R¹ _(a) in Formula III_(a). X_(d) is a monovalent radical, preferably a hydrogen atom, and, in the case where n_(d) equals 1, can also be a hydroxyl, methoxy or ethoxy group or a fluorine atom.

[0048] Identity of E

[0049] E is a prolyl, thiazolidinyl-4-carbonyl, homoprolyl or hydroxyprolyl residue, or a cyclic α-amino carboxylic acid residue of Formula II_(e),

[0050] where n_(e) is an integer, preferably 0, 1 or 2. R¹ _(e) has the meaning stated for R¹ _(a) in Formula III_(a). R² _(e) and R³ _(e) are each a monovalent radical, and can be, independently, a hydrogen atom or a methyl group. R⁴ _(e) is a monovalent radical, preferably a hydrogen atom, a hydroxyl, methoxy or ethoxy group or a fluorine atom. R⁵ _(e) is a monovalent radical, preferably a hydrogen atom. In the case where n_(e) has the value 1, R³ _(e) and R⁴ _(e) together can form a double bond or R⁴ _(e) and R⁵ _(e) can together be a double-bonded oxygen radical. In the case where n_(e) has the value 1 or 2, R¹ _(e) and R² _(e) can together form a double bond.

[0051] In another embodiment, E is a 2- or 3-amino-cyclopentanecarboxylic acid residue of Formula III_(e),

[0052] where R_(e) is a monovalent radical, such as a methyl or ethyl group and R¹ _(e) has the meaning stated for R¹ _(a) in Formula III_(a).

[0053] Identity of F

[0054] In one embodiment, F is an aminobenzoyl derivative of Formula II_(f),

[0055] where R_(f) is a hydrogen atom or an alkyl group, preferably a methyl, ethyl or propyl group. The carbonyl group can be in position 1 (ortho), 2 (meta), or 3 (para) of the phenyl ring relative to the nitrogen atom. R¹ _(f) and R² _(f) are each, independently, a hydrogen atom; a halogen atom, for example, a fluorine, chlorine, bromine, or iodine atom; a C₁-C₄-alkyl group; a methoxy, ethoxy, trifluoromethyl, nitro, cyano, amino or dimethyalmino group. Additionally, R¹ _(f) and R² _(f) can together form a dioxymethylene group.

[0056] In another embodiment, F is an aminocycloalkanecarboxylic acid residue of Formula III_(f),

[0057] where R_(f) is a monovalent radical, such as a hydrogen atom or a lower alkyl group, preferably a methyl, ethyl or propyl group. a_(f) is an integer, for example, 0, 1 or 2. The carbonyl group is in position 2 or position 3 of the cycloalkane ring relative to the nitrogen atom at position 1. The stereogenic centers can be, independently of each other, R or S. For a five-membered ring (a_(f)=1) , the combinations R1,S2 and S1,R2 would be referred to as cis-pentacin derivatives, while the combinations R1,R2 and S1,S2 are trans-pentacin derivatives.

[0058] Identity of G

[0059] In one embodiment, G is an amino or substituted amino group of Formula II_(g),

[0060] where R¹ _(l) is a monovalent radical, such as a hydrogen atom, a normal or branched, saturated or unsaturated C₁-C₁₈-alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted aryl-C₁-C₆-alkoxy group, or a substituted or unsubstituted aryloxy-C₁-C₆-alkoxy or heteroaryl-C₁-C₆-alkoxy group. The aryl group is preferably a phenyl or naphthyl group. The heteroaryl group is a 5- or 6-membered, preferably nitrogen-, oxygen- or sulfur-containing, ring system, such as, for example, imidazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, pyrazolyl, thiophenyl, furanyl, pyrrolyl, 1,2,4- or 1,2,3-triazolyl, pyrazinyl, indolyl, benzofuranyl, benzothiophenyl, isoindolyl, indazolyl, quinolinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzopyranyl, benzothiazolyl, oxadiazolyl, thiadiazolyl or pyridinyl group. Suitable aryl or heteroaryl substituents include one or more halogen atoms, preferably fluorine, bromine or chlorine; C₁-C₄-alkyl groups; methoxy, ethoxy or trifluoromethyl groups, a dioxymethylene group or a nitro group.

[0061] R² _(l) is a monovalent radical, such as a hydrogen atom, a normal or branched, saturated or unsaturated C₁-C₁₈-alkyl group, a C₃-C₁₀-cycloalkyl group, a substituted or unsubstituted aryl group, where aryl is preferably phenyl or naphthyl. Suitable aryl substituents include one or more halogen, preferably fluorine, chlorine or bromine, atoms, C₁-C₄-alkyl groups, methoxy, ethoxy or trifluoromethyl groups, a dioxymethylene group, nitro or cyano groups, a C₁-C₇-alkoxycarbonyl group, a C₁-C₇-alkylsulfonyl group, an amino or C₁-C₇-dialkylamino group, where the alkyl groups can, together with the nitrogen atom, also form a 5- or 6-membered heterocycle, or an unsubstituted or substituted heteroaryl group. The heteroaryl group can be a 5- or 6-membered, preferably nitrogen-, oxygen- or sulfur-containing, ring system which can be fused to a benzene ring, such as, for example, imidazolyl, pyrrolyl, thiophenyl, furanyl, thiazolyl, oxazolyl, pyrazolyl, 1,2,4- or 1,2,3-triazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzopyranyl, indolyl, isoindolyl, indazolyl or quinolinyl group, with preferred substituents being C₁-C₆-alkyl groups, or hydroxyl or phenyl groups.

[0062] R² _(l) can additionally be of Formula II_(l),

[0063] wherein a_(l) is an integer, preferably 0, 1, 2, 3, 4, or 5. R³ _(l) is a monovalent radical, such as a lower alkyl group, for example, a methyl, ethyl, propyl or isopropyl group. R⁴ _(l) is a saturated or partially unsaturated carbocyclic group containing from 3 to about 10 carbon atoms, or a substituted or unsubstituted aryl or heteroaryl group, where the preferred aryl and heteroaryl groups and suitable substituents are as stated for R² _(l) in Formula II_(g).

[0064] R² _(l) can also be a monovalent radical of Formula III_(l),

[0065] wherein W_(l) is an oxygen or sulfur atom or an N—R⁶ _(l) group. R⁵ _(l) is a monovalent radical, such as a hydrogen atom, a C₁-C₄-alkyl or C₃-C₇-cycloalkyl group or a substituted or unsubstituted aryl or arylmethyl group, with aryl and its preferred substituents having the meaning stated for R² _(l) from Formula II_(g). R⁶ _(l) is a monovalent radical, preferably a hydrogen atom, a C₁-C₄-alkyl group or a C₃-C₇-cycloalkyl group, a C₁-C₁₈-alkanoyl group, a benzoyl group or a substituted or unsubstituted aryl or arylmethyl group, with aryl and its preferred substituents having the meaning stated for R² _(l) in Formula II_(g),

[0066] R² _(l) can alternately be a substituent of Formula IV_(l),

[0067] where b_(l) is an integer, preferably 2, 3 or 4. Z_(l) is a monovalent radical, such as a formyl, aminocarbonyl or hydrazinocarbonyl group, or a cyclic or acyclic acetal or thioacetal group.

[0068] R² _(l) can also be a substituent of Formula V_(l),

[0069] in which b_(l) is an integer, preferably 2, 3 or 4. R⁷ _(l) is a monovalent radical, such as a glycol oligomer of the formula

—O(CH₂CH₂O)_(dl)—CH₃,

[0070] where d_(l) is an integer, preferably in the range from about 2 to about 4 or from about 40 to about 90.

[0071] R² _(l) can further be a carbohydrate of Formula VI_(l),

[0072] where R⁸ _(l) is a monovalent radical, such as a hydrogen atom, a C₁-C₄-alkanoyl or alkyl group, a benzoyl group or a benzyl group.

[0073] In another embodiment, G is an β-hydroxy amine of Formula III_(g),

[0074] where R⁹ _(l) is a monovalent radical such as a hydrogen atom, a C₁-C₆-alkyl group or a substituted or unsubstituted aryl group, with aryl and its preferred substituents having the meaning stated for R² _(l) in Formula II_(g). R¹⁰ _(l) is a monovalent radical, preferably a hydrogen atom, alkyl, for example, methyl, or a phenyl group.

[0075] Another subclass of compounds of this invention includes peptides of Formula I wherein G is a hydrazido group of Formula IV_(g),

[0076] where R¹¹ _(l) and R¹² _(l) are each, independently, a monovalent radical such as a hydrogen atom, a normal or branched C₁-C₈-alkyl group, a C₃-C₈- cycloalkyl group, a C₃-C₈-cycloalkyl-C₁-C₄-alkyl group or a substituted or unsubstituted aryl, heteroaryl, aryl-C₁-C₄-alkyl or heteroaryl-C₁-C₄-alkyl group, where aryl, heteroaryl and their preferred substituents can be selected from among the options listed for R² ₁ in Formula II_(g). R¹¹ _(l) and R¹² _(l) can also together form a propylene or butylene bridge.

[0077] Another subclass of compounds of this invention includes peptides of Formula I wherein G is a monovalent radical of the formula —O—R¹³ _(l) or —S—R¹³ _(l), where R¹³ _(l) is a monovalent radical, such as a C₃-C₁₀-cycloalkyl group, a normal or branched C₂-C₁₆-alkenylmethyl group or a C₁-C₁₆-alkyl group which can be substituted by from 1 to about 5 halogen, preferably fluorine, atoms.

[0078] R¹³ _(l) can also be the radical —(CH₂)_(el)—R¹⁴ _(l) where e_(l) is an integer, preferably 1, 2 or 3. R¹⁴ _(l) is a monovalent radical, preferably a saturated or partially unsaturated C₃-C₁₀-carbocycle.

[0079] R¹³ _(l) can further be the radical

—[CH₂—CH═C(CH₃)—CH₂]_(fl)—H,

[0080] where f_(l) is an integer, preferably 1, 2, 3 or 4.

[0081] R¹³ _(l) can also be the radical

—[CH₂—CH₂—O]_(gl)—CH₃,

[0082] where g_(l) is an integer, preferably from about 2 to about 4, or from about 40 to about 90.

[0083] R¹³ _(l) can also be the radical

—(CH₂)_(hl)-aryl or —(CH₂)_(hl)-heteroaryl,

[0084] where aryl and heteroaryl can also be substituted and, along with their preferred substituents, can be selected from the group listed for R² _(l) in Formula II_(g). h_(l) is an integer, preferably 0, 1, 2 or 3.

[0085] R¹³ _(l) can further be the radical

—(CH₂)_(bl)-W_(l)-R⁵ _(l),

[0086] where b_(l), W_(l) and R⁵ _(l) are each selected from among the options described for Formula III_(l).

[0087] Another subclass of compounds of this invention includes peptides of Formula I in which G is an aminoxy group of the formula

—O—N(R¹⁵ _(l))(R¹⁶ _(l)),

[0088] where R¹⁵ _(l) and R¹⁶ _(l) are each a monovalent radical, and can independently be a hydrogen atom, a normal or branched C₁-C₈-alkyl group, which can be substituted by halogen, preferably fluorine, atoms, a C₃-C₈-cycloalkyl group, a C₃-C₈-cycloalkyl-C₁-C₄-alkyl group, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted aryl-C₁-C₄-alkyl group. Aryl and heteroaryl groups and the preferred substituents thereof can be selected from the options listed for R² _(l) in Formula II_(g). Additionally, R¹⁵ _(l) and R¹⁶ _(l) can together form a 5-, 6- or 7-membered heterocycle.

[0089] Another subclass of compounds of this invention includes peptides of Formula I wherein G is an oximato group of the formula

—O—N═C(R¹⁵ _(l))(R¹⁶ _(l)),

[0090] where R¹⁵ _(l) and R¹⁶ _(l) are selected from among the options listed above and, additionally, can together form a cyclic system comprising, preferably, from about 3 to about 7 ring atoms. This cyclic system can additionally be fused to one or more aromatic rings. Particularly preferred cyclic systems are shown below.

[0091] A further subclass of compounds of this invention includes peptides of Formula I wherein G is a hydrogen atom, a normal or branched C₁-C₈-alkyl group, which can be substituted by up to six halogen, preferably fluorine, atoms, a C₃-C₈-cycloalkyl group or a C₃-C₈-cycloalkyl-C ₁-C₄-alkyl group.

[0092] G can also be an arylalkyl, heteroarylalkyl, aryl or heteroaryl group of Formula V_(g),

—(CH₂)_(ag)—R¹⁷ _(l)  (V_(g))

[0093] where a_(g) is an integer, such as 0, 1 or 2. R¹⁷ _(l) is a substituted or unsubstituted aryl or heteroaryl group. Preferred aryl groups include phenyl and naphthyl groups. Suitable aryl substituents include halogen, preferably fluorine, bromine or chlorine, atoms, C₁-C₄-alkyl groups, methoxy, ethoxy or trifluoromethyl groups, a dioxymethylene group, a nitro or cyano group, a C₁-C₇-alkoxycarbonyl group, a C₁-C₇- alkylsulfonyl group, an amino group or a C₁-C₆-dialkylamino group, where the alkyl groups can, together with the nitrogen atom, also form a 5- or 6-membered heterocycle. R¹⁷ _(l) can also be a 5- or 6-membered, preferably nitrogen-, oxygen- or sulfur-containing, ring system which can be fused to a benzene ring. Suitable heteroaryl groups include imidazolyl, pyrrolyl, thiophenyl, furanyl, thiazolyl, oxazolyl, pyrazolyl, 1,2,4- or 1,2,3-triazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzopyranyl, indolyl, isoindolyl, indazolyl and quinolinyl groups. Preferred heteroaryl substituents are C₁-C₆-alkyl groups, a hydroxyl group or a phenyl group.

[0094] Another subclass of compounds of this invention includes compounds of Formula I wherein G is a monovalent radical of Formula VI_(g),

—(CH₂)_(bg)—(C═O)_(cg)—OR¹⁸ _(l)  (VI_(g)),

[0095] where b_(g) is an integer, preferably 0, 1, 2 or 3, and c_(g) is an integer, preferably 0 or 1. b_(g) and c_(g) are not both simultaneously 0. R¹⁸ _(l) is a monovalent radical, such as a hydrogen atom, a straight-chain or branched C₁-C₈-alkyl group which can be substituted by halogen, preferably fluorine, atoms, especially a CF₂-moiety, a C₃-C₈-cycloalkyl group, a C₃-C₈-cycloalkyl-C₁-C₄-alkyl group, a substituted or unsubstituted aryl, preferably phenyl or naphthyl, group. Suitable aryl substituents are halogen, preferably fluorine, bromine or chlorine, atoms, C₁-C₄-alkoxy, trifluoromethyl, nitro or cyano groups, a dioxymethylene moiety, a C₁-C₇-alkoxycarbonyl moiety, a C₁-C₇-alkylsulfonyl moiety, an amino group or a C₁-C₆-dialkylamino group, where the alkyl groups can, together with the nitrogen atom, also form a 5- or 6-membered heterocycle.

[0096] G can also be a monovalent radical of Formula VII_(g)

[0097] where d_(g) is an integer, preferably 0, 1, 2 or 3, and e_(g) is an integer such as 0 or 1. d_(g) and e_(g) cannot both simultaneously take the value 0. R¹⁹ _(l) and R²⁰ _(l) are each, independently, a monovalent radical, such as a hydrogen atom, a straight-chain or branched C₁-C₈-alkyl group, which can further be substituted by halogen, preferably fluorine, atoms, especially a CF₂-moiety, a C₃-C₈-cycloalkyl group, a C₃-C₈-cycloalkyl-C₁-C₄-alkyl group, a substituted or unsubstituted aryl, preferably phenyl or naphthyl group. Suitable aryl substituents include one or more halogen, referably fluorine, bromine or chlorine, atoms, C₁-C₄-alkoxy, trifluoromethyl, nitro or cyano groups, a dioxymethylene moiety, a C₁-C₇-alkoxycarbonyl moiety, a C₁-C ₇-alkylsulfonyl group, an amino group or a C₁-C₆-dialkylamino group, where the alkyl groups can, together with the nitrogen atom, also form a 5- or 6-membered heterocycle. N(R¹⁹ _(l))R²⁰ _(l) can additionally form a ring system of the formula N(CH₂)_(fg), where f_(g) is an integer selected from among 4, 5 or 6.

[0098] Another subclass of compounds of this invention includes peptides of Formula I, wherein G is a monovalent radical of Formula VIII_(g),

—(CH₂)_(gg)—S(O)_(hg)—R²¹ _(l)  (VIII_(g)),

[0099] where g_(g) is an integer, for example, 1 or 2, and h_(g) is 1 or 2. R²¹ _(l) is a monovalent radical, preferably a methyl group, a trifluoromethyl group, an ethyl group or a phenyl group.

[0100] G can also be an alkyl- or arylcarbonylalkyl group of Formula IX_(g),

—(CH₂)_(ig)—(C═O)—R²² _(l)  (IX_(g)),

[0101] where R²² _(l) is a monovalent radical, such as a hydrogen atom, a straight-chain or branched C₁-C₈-alkyl group which can be substituted by up to six halogen, preferably fluorine, atoms, especially a CF₂-moiety, a C₃-C₈-cycloalkyl group, a C₃-C₈-cycloalkyl-C₁-C₄-alkyl group, a substituted or unsubstituted aryl, preferably phenyl or naphthyl, group. Suitable aryl substituents are halogen, preferably fluorine, bromine or chlorine, atoms, C₁-C₄-alkoxy, trifluoromethyl, nitro or cyano groups, a dioxymethylene moiety, a C₁-C₇-alkoxycarbonyl moiety, a C₁-C₇-alkylsulfonyl moiety, an amino group or a C₁-C₆-dialkylamino group, where the alkyl groups can, together with the nitrogen atom, also form a 5- or 6-membered heterocycle.

[0102] Synthetic Methods

[0103] The compounds of the present invention can be prepared by known methods of peptide synthesis. Thus, the peptides can be assembled sequentially from individual amino acids or by linking suitable small peptide fragments. In sequential assemblage, the peptide chain is extended stepwise, starting at the C-terminus, by one amino acid per step. In fragment coupling, fragments of different lengths can be linked together, and the fragments in turn can be obtained by sequential assembly from amino acids or by fragment coupling of still shorter peptides.

[0104] In both sequential assemblage and fragment coupling it is necessary to link the units by forming an amide linkage, which can be accomplished via a variety of enzymatic and chemical methods. Chemical methods for forming the amide linkage are described in detail in standard references on peptide chemistry, including Müller, Methoden der organischen Chemie Vol. XV/2, pages 1-364, Thieme Verlag, Stuttgart, Germany (1974); Stewart and Young, Solid Phase Peptide Synthesis, pages 31-34 and 71-82, Pierce Chemical Company, Rockford, Ill. (1984); Bodanszky et al., Peptide Synthesis, pages 85-128, John Wiley & Sons, New York, (1976). Preferred methods include the azide method, the symmetric and mixed anhydride method, the use of in situ generated or preformed active esters, the use of urethane protected N-carboxy anhydrides of amino acids and the formation of the amide linkage using coupling reagents, such as carboxylic acid activators, especially dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), pivaloyl chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), n-propane-phosphonic anhydride (PPA), N,N-bis(2-oxo-oxazolidinyl)imido-phosphoryl chloride (BOP-Cl), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop), diphenyl-phosphoryl azide (DPPA), Castro's reagent (BOP, PyBop), O-benzotriazolyl-N,N,N′, N′-tetramethyluronium salts (HBTU), diethylphosphoryl cyanide (DEPCN), 2,5-diphenyl-2,3-dihydro-3-oxo-4-hydroxy-thiophene dioxide (Steglich's reagent; HOTDO), and 1,1′-carbonyl-diimidazole (CDI). The coupling reagents can be employed alone or in combination with additives such as N,N-dimethyl-4-aminopyridine (DMAP), N-hydroxy-benzotriazole (HOBt), N-hydroxybenzotriazine (HOOBt), N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine.

[0105] Although the use of protecting groups is generally not necessary in enzymatic peptide synthesis, reversible protection of reactive groups not involved in formation of the amide linkage is necessary for both reactants in chemical synthesis. Three conventional protective group techniques are preferred for chemical peptide synthesis: the benzyloxycarbonyl (Z), the t-butoxycarbonyl (Boc) and the 9-fluorenylmethoxycarbonyl (Fmoc) techniques. Identified in each case is the protective group on the α-amino group of the chain-extending unit. A detailed review of amino-acid protective groups is given by Müller, Methoden der organischen Chemie Vol. XV/1, pp 20-906, Thieme Verlag, Stuttgart (1974). The units employed for assembling the peptide chain can be reacted in solution, in suspension or by a method similar to that described by Merrifield (J. Am. Chem. Soc. 85: 2149 (1963)). Particularly preferred methods are those in which peptides are assembled sequentially or by fragment coupling using the Z, Boc or Fmoc protective group technique, with one of the reactants in the said Merrifield technique being bonded to an insoluble polymeric support (also called resin hereinafter). This typically entails assembling the peptide sequentially on the polymeric support using the Boc or Fmoc protective group technique, with the growing peptide chain covalently bonded at the C terminus to the insoluble resin particles. This procedure allows the removal of reagents and byproducts by filtration, eliminating the need to recrystallize intermediates.

[0106] The protected amino acids can be linked to any suitable polymer, which must be insoluble in the solvents used and have a stable physical form which permits filtration. The polymer must contain a functional group to which the first protected amino acid can be covalently attached. A wide variety of polymers are suitable for this purpose, including cellulose, polyvinyl alcohol, polymethacrylate, sulfonated polystyrene, chloromethylated styrene/divinylbenzene copolymer (Merrifield resin), 4-methylbenzhydrylamine resin (MBHA-resin), phenylacetamidomethyl resin (Pam-resin), p-benzyloxy-benzyl-alcohol-resin, benzhydryl-amine-resin (BHA-resin), 4-(hydroxymethyl)-benzoyl-oxymethyl-resin, the resin of Breipohl et al. (Tetrahedron Letters 28 (1987) 565; supplied by BACHEM), 4-(2,4-dimethoxyphenylaminomethyl) phenoxy resin (supplied by Novabiochem) or o-chlorotrityl-resin (supplied by Biohellas).

[0107] Solvents suitable for peptide synthesis include any solvent which is inert under the reaction conditions, especially water, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dichloromethane (DCM), 1,4-dioxane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP) and mixtures of these solvents.

[0108] Peptide synthesis on the polymeric support can be carried out in a suitable inert organic solvent in which the amino acid derivatives starting materials are soluble. However, preferred solvents additionally have resin-swelling properties and include DMF, DCM, NMP, acetonitrile, DMSO, and mixtures of these solvents. Following synthesis, the peptide is removed from the polymeric support. The conditions under which this cleavage is accomplished for various resin types are disclosed in the literature. The cleavage reactions most commonly used are acid- or palladium-catalyzed, the former being conducted in, for example, liquid anhydrous hydrogen fluoride, anhydrous trifluoromethanesulfonic acid, dilute or concentrated trifluoroacetic acid, and acetic acid/dichloromethane/trifluoroethanol mixtures. The latter can be carried out in THF or THF-DCM-mixtures in the presence of a weak base such as morpholine. Certain protecting groups are also cleaved off under these conditions.

[0109] Partial deprotection of the peptide may also be necessary prior to certain derivatization reactions. For example, peptides dialkylated at the N-terminus can be prepared either by coupling the appropriate N,N-di-alkylamino acid to the peptide in solution or on the polymeric support or by reductive alkylation of the resin-bound peptide in DMF/1% acetic acid with NaCNBH₃ and the appropriate aldehyde.

[0110] The two schemes which follow present a more detailed description of the synthesis of the compounds of the present invention.

[0111] The tetrapeptide A-B-D-E-OH is coupled with an amino-derivative F-G to give the final compound A-B-D-E-F-G using the methods for peptide coupling as described above.

[0112] Here, the N-terminal protected tetrapeptide A′-B-D-E-OH is coupled with an amino-derivative F-G to give an intermediate compound A′-B-D-E-F-G using the methods for peptide coupling as described above. Then, the N-protecting group is removed by conventional methods as described above. The groups R_(A) and R⁷ _(A) can then be attached to the amino terminus via reductive alkylation as described above.

[0113] Building blocks of use in the synthesis of the claimed compounds (described in scheme I and II as F-G) can be prepared by the following general methods:

[0114] a) Synthesis of Amino-phenyl-ketones

[0115] The following schemes describe synthetic routes to aminophenyl-ketones which are not commercially available.

[0116] In scheme III.1, the synthesis starts with a nitrobenzaldehyde. Addition of organometallic compounds such as lithium or Grignard reagents led to the corresponding alcohols (Fürstner et al. Tetrahedron 52: 7329-7344 (1996); Fürstner et al., Tetrahedron 51, 773-786 (1995)). These alcohols can be oxidised to the ketones with known oxidation agents, such as chromium(VI) compounds (for example, pyridinium dichromate in dichloromethane, as described by Fürstner et al., supra) or the Dess Martin reagent. The nitrophenyl ketones are then reduced to the corresponding amino-phenyl-ketones either by hydrogenation in presence of a palladium catalyst, such as palladium on carbon, or by metal salts in presence of acids such as the combination of tin(II)chloride and hydrochloric acid (Nunn et al., J. Chem. Soc. 1952: 583-588).

[0117] A more direct route (see scheme III.2) is the reaction of nitrobenzoyl chlorides with an organometallic reagent such as a lithium or Grignard reagent (Fürstner et al., Tetrahedron 51, 773-786 (1995)).

[0118] 2-Amino-phenyl ketones can be obtained by reaction of the corresponding 2-fluorophenyl-ketone with sodium azide in a polar solvent, such as N,N-dimethylformamide, and subsequent reduction of the intermediate benzisoxazole (see scheme III.3). For example, the synthesis of 2-aminophenyl-(4-pyridazinyl)-ketone has been described by N. Haider et al. (Arch. Pharm. 325: 119-122 (1992)).

[0119] b) Synthesis of Amino-benzamides

[0120] The following schemes describe synthetic routes to aminobenzamides which are not commercially available.

[0121] In scheme IV.1, the steps are described starting from nitrobenzoic acids or substituted nitrobenzoic acids. These acids are coupled with primary or secondary amines (HNR¹R²) by using coupling reagents. Preferred method is the use of coupling reagents such as carboxylic acid activators, especially dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), pivaloylchloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), n-propane-phosphonic anhydride (PPA), N,N-bis(2-oxo-3oxazolidinyl)-imidophosphoryl chloride (BOP-Cl), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop), diphenylphosphoryl azide (DPPA), Castro's reagent (BOP, PyBop), O-benzotriazolyl-N,N,N′,N′-tetramethyluronium salts (HBTU), diethylphosphoryl cyanide (DEPCN), 2,5-diphenyl 2,3-dihydro-3-oxo-4-hydroxythiophene dioxide (Steglich's reagent; HOTDO) and 1,1′-carbonyldiimidazole (CDI). The coupling reagents can be employed alone or in combination with additives such as N,N-dimethyl-4-aminopyridine (DMAP), N-hydroxy-benzotriazole (HOBt), N-hydroxybenzotriazine (HOOBt), azabenzotriazole, N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine.

[0122] In place of the acids, the corresponding nitro-benzoyl chloride can be used. These are either commercially available or could be synthesized from the corresponding acids with thionyl chloride. The amines react with the nitrobenzoylchlorides in the presence of a base such as pyridine, which can also be used as the solvent (N. S. Cho et al., J. Heterocycl. Chem. 33, 1201-1206 (1996)). The nitro-benzamides are then reduced to the corresponding amino-benzamides by reducing agents such as metal salts in presence of hydrochloride acids or by metal-catalysed hydrogenation using palladium on a solid such as palladium on charcoal as catalyst. This route is described in Example 1.

[0123] Another method involves transforming the amine to the trifluoroacetamide by treatment with trifluoroacetic anhydride. The amide is deprotonated with a base such as sodium hydride or potassium t-butanolate and then treated with the corresponding alkyl halide such as methyl iodide, ethyl iodide or isopropyl iodide. The trifluoroacetamide is easily cleaved in basic alcoholic solution such as potassium carbonate in methanol.

[0124] In scheme IV.2. the starting materials for the synthesis of amino-benzamides are the N-protected aminobenzoic acids. Different protecting groups for the nitrogen are compatible such as the above mentioned Z-, Boc- or Fmoc-protecting groups. The N-protected amino-benzoic acids are coupled with amines as described above for the nitro-benzoic acids using the above mentioned coupling conditions. This route is exemplified in Example 2.

[0125] A route for the preparation of 2-aminobenzamides is described in scheme IV.3. Opening of isatoic anhydride (substituted or unsubstituted at the nitrogen) by amines with evolution of carbon dioxide led to the corresponding 2-amino-benzamides, as described by Clark et al., J. Org. Chem. 9: 55-64 (1944).

[0126] c) Amino-cyclopentane- or Aminocyclohexane-carboxamides

[0127] Different routes have been described to the synthesis of cis-2-amino-cyclopentylcarboxylic acid (cispentacin) in racemic form or as pure enantiomer. Using an intramolecular nitrone-olefin cycloaddition cis-2-(t-butoxycarbonylamino)cyclopentane-1-carboxylic acid could be prepared in a few synthetic steps (Konosu et al., Chem. Pharm. Bull. 41: 1012 (1993)). Another route to enantiomerically pure cis-(1R, 2S)-2-amino-cyclopentylcarboxylic acid is the addition of chiral lithium (S)-(-methylbenzyl)benzylamide to t-butyl-1-cyclopentene-1-carboxylate with subsequent removal of the benzyl groups by hydogenation and removal of the t-butyl group by acid treatment (Davies et al., Synlett 1993, p. 461). The corresponding trans-epimer could be obtained by isomerisation with a base such as potassium t-butoxide. By using the lithium (R)-(-methylbenzyl)benzylamide in the Michael addition (1S, 2R)-2-amino-cyclopentylcarboxylic acid and (1S, 2S)-2-amino-cyclopentylcarboxylic acid can be obtained. This method is also applicable to the synthesis of cis-and trans-aminocyclohexane-1-carboxylic acid.

[0128] Resolution of racemic Boc-protected cis-2-aminocyclopentane carboxylic acid (Bernath et al., Acta Chim. 74: 479 (1972); Nativ et al., Isr. J. Chem. 10: 55 (1972)) can be achieved with (+)- and (−)-ephedrine in high enantiomeric excess (Nöteberg et al., Tetrahedron 53: 7975 (1997)). In this paper also the synthesis of the trans-enantiomers of Boc-protected trans-2-aminocyclopentane carboxylic methyl ester was described, starting with either trans-(3R, 4R)-bis(methoxycarbonyl)cyclopentanone or trans(3S,4S)-bis(methoxycarbonyl)-cyclopentanone.

[0129] Amides of Boc-protected 2-aminocyclopentylcarboxylic acid can be obtained by coupling the acid with the corresponding amine using the standard procedures as described above for the coupling of nitrobenzoic acid with amines or as described in D. Nöteberg et al., Tetrahedron 53: 7975 (1997). Deprotection of the amine function can be achieved by using Lewis acids, for example, a mineral acid such as hydrochloric acid in ether or dioxane or an organic acid, such as trifluoroacetic acid in methylene chloride.

[0130] Methods of Use of the Claimed Compounds

[0131] In another embodiment, the present invention comprises a method for partially or totally inhibiting formation of, or otherwise treating (e.g., reversing or inhibiting the further development of) solid tumors (e.g., tumors of the lung, breast, colon, prostate, bladder, rectum, or endometrial tumors) or hematological malignancies (e.g., leukemias, lymphomas) in a mammal, for example, a human, by administering to the mammal a therapeutically effective amount of a compound or a combination of compounds of Formula I. The agent may be administered alone or in a pharmaceutical composition comprising the agent and an acceptable carrier or diluent. Administration may be by any of the means which are conventional for pharmaceutical, preferably oncological, agents, including oral and parenteral means such as subcutaneously, intravenously, intramuscularly and intraperitoneally, nasally or rectally. The compounds may be administered alone or in the form of pharmaceutical compositions containing a compound of Formula I together with a pharmaceutically accepted carrier appropriate for the desired route of administration. Such pharmaceutical compositions may be combination products, i.e., they may also contain other therapeutically active ingredients.

[0132] The dosage to be administered to the mammal, such as a human, will contain a therapeutically effective amount of a compound described herein. As used herein, “therapeutically effective amount” is an amount sufficient to inhibit (partially or totally) formation of a tumor or a hematological malignancy or to reverse development of a solid tumor or other malignancy or prevent or reduce its further progression. For a particular condition or method of treatment, the dosage is determined empirically, using known methods, and will depend upon factors such as the biological activity of the particular compound employed; the means of administration; the age, health and body weight of the recipient; the nature and extent of the symptoms; the frequency of treatment; the administration of other therapies; and the effect desired. A typical daily dose will be from about 5 to about 250 milligrams per kilogram of body weight by oral administration and from about 1 to about 100 milligrams per kilogram of body weight by parenteral administration.

[0133] The compounds of the present invention can be administered in conventional solid or liquid pharmaceutical administration forms, for example, uncoated or (film-)coated tablets, capsules, powders, granules, suppositories or solutions. These are produced in a conventional manner. The active substances can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, sustained release compositions, antioxidants and/or propellant gases (cf. H. Sücker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way typically contain from about 1 to about 90% by weight of the active substance.

[0134] The following examples are intended to illustrate the invention but are not to be considered limitations of the invention.

EXAMPLES

[0135] The proteinogenous amino acids are abbreviated in the examples using the known three-letter code. Other abbreviations employed are: TFA=trifluoroacetic acid, Ac= acetic acid, DCM=dichloromethane, DMSO= dimethylsulfoxide, Bu=butyl, Et=ethyl, Me=methyl, Bn= benzyl. In the compounds listed, all proteinogenous amino acids are L-amino acids unless otherwise noted.

[0136] General Materials and Methods

[0137] The compounds of the present invention are synthesized by classical solution synthesis using standard Z- and Boc-methodology as discussed above or by standard methods of solid-phase synthesis on a model 431A synthesizer supplied by APPLIED BIOSYSTEMS. This apparatus uses different synthetic cycles for the Boc and Fmoc protective group techniques, as described below. Synthetic cycle for the Boc protecting group technique 1. 30% trifluoroacetic acid in DCM 1 × 3 min 2. 50% trifluoroacetic acid in DCM 1 × 1 min 3. DCM washing 5 × 1 min 4. 5% diisopropylethylamine in DCM 1 × 1 min 5. 5% diisopropylethylamine in NMP 1 × 1 min 6. NMP washing 5 × 1 min 7. Addition of preactivated  1 × 30 min protected amino acid (activation with 1 equivalent of DCC and 1 equivalent of HOBt in NMP/DCM); Peptide coupling (1st part) 8. Addition of DMSO to the reaction mixture until it contains 20% DMSO by volume 9. Peptide coupling (2nd part)  1 × 16 min 10. Addition of 3.8 equivalents of diisopropylethylamine to the reaction mixture 11. Peptide coupling (3rd part) 1 × 7 min 12. DCM washing 3 × 1 min 13. if conversion is incomplete, repetition of coupling (back to step 5) 14. 10% acetic anhydride, 5% diisopropylethylamine in DCM 1 × 2 min 15. 10% acetic anhydride in DCM 1 × 4 min 16. DCM washing 4 × 1 min 17. back to step 1.

[0138] BOP-Cl and PyBrop were used as reagents for coupling an amino acid to an N-methylamino acid. The reaction times were correspondingly increased. In solution synthesis, the use of either Boc-protected amino acid NCAs (N-tert-butyloxycarbonyl-amino acid-N-carboxy-anhydrides) or Z-protected amino acid NCAs (N-benzyloxycarbonyl-amino acid-N-carboxy-anhydrides) respectively is most preferable for this type of coupling. Synthetic cycle for the Fmoc protective group technique 1. DMF washing 1 × 1 min 2. 20% piperidine in DMF 1 × 4 min 3. 20% piperidine in DMF  1 × 16 min 4. DMF washing 5 × 1 min 5. Addition of the preactivated  1 × 61 min protected amino acid (activation by 1 equivalent of TBTU and 1.5 equivalent of DIPEA in DMF); Peptide coupling 6. DMF washing 3 × 1 min 7. If conversion is incomplete, repetition of coupling (back to 5.) 8. 10% acetic anhydride in DMF 1 × 8 min 9. DMF washing 3 × 1 min 10. back to 2.

[0139] BOP-Cl and PyBrop were used as reagents for coupling an amino acid to an N-methylamino acid. The reaction times were correspondingly increased.

[0140] Reductive Alkylation of the N Terminus

[0141] The peptide-resin prepared as described above was deprotected at the N terminus and then reacted with a 3-fold molar excess of aldehyde or ketone in DMF/1% acetic acid with addition of 3 equivalents of NaCNBH₃. After reaction was complete (negative Kaiser test), the resin was washed several times with water, isopropanol, DMF and dichloromethane.

[0142] Workup of the Peptide-Resins

[0143] The peptide-resin obtained via the Boc protecting group technique was dried under reduced pressure and transferred into a reaction vessel of a TEFLON HF apparatus (supplied by PENINSULA). A scavenger, usually anisole (1 mL/g of resin), was then added and additionally, in the case of tryptophan-containing peptides, a thiol (0.5 mL/g of resin), preferably ethanedithiol, to remove the indolic formyl group. This was followed by condensing in hydrogen fluoride (10 mL/g of resin) in a bath of liquid N₂. The mixture was allowed to warm to 0° C. and stirred at this temperature for 45 min. The hydrogen fluoride was then stripped off under reduced pressure, and the residue was washed with ethyl acetate to remove any remaining scavenger. The peptide was extracted with 30% acetic acid and filtered, and the filtrate was lyophilized.

[0144] The peptide-resin formed by the Fmoc protecting group method was dried under reduced pressure and then subjected to one of the following cleavage procedures, depending upon the amino-acid composition (Wade, Tregear, Howard Florey Fmoc Workshop Manual, Melbourne 1985). The suspension of the peptide-resin in the suitable TFA mixture was stirred at room temperature for the stated time and then the resin was filtered off and washed with TFA and DCM. The filtrate and the washings were concentrated, and the peptide was precipitated by addition of diethyl ether. After cooling in an ice bath, the precipitate was filtered off, taken up in 30% acetic acid and lyophilized.

[0145] When an o-chlorotrityl-resin (supplied by Biohellas) was used, the suspension of the peptide-resin in an acetic acid/trifluoroethanol/dichloromethane mixture (1:1:3) was stirred at room temperature for 1 h. The suspension was then filtered with suction and the peptide-resin was thoroughly washed with the cleavage solution. The combined filtrates were concentrated in vacuo and treated with water. The precipitated solid was removed by filtration or centrifugation, washed with diethyl ether and dried under reduced pressure.

[0146] Purification and Characterization of the Peptides

[0147] Purification was carried out by gel chromatography (SEPHADEX G-10, G-15/10% HOAc, SEPHADEX LH20/MeOH) with or without subsequent medium pressure chromatography (stationary phase: HD-SIL C-18, 20-45 m, 100 Å; mobile phase: gradient with A=0.1% TFA/MeOH, B=0.1% TFA/H2O). The purity of the resulting products was determined by analytical HPLC (stationary phase: 100 2.1 mm VYDAC C-18, 5 l, 300 Å; mobile phase: CH₃CN/H₂O gradient, buffered with 0.1% TFA, 40%C).

[0148] The polypeptides were characterized by amino-acid analysis and fast atom bombardment mass spectroscopy.

EXAMPLE 1 Synthesis of (2)-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄—CON(CH₃)₂ (Compound I-78)

[0149] Me₂Val-Val-MeVal-Pro-OH and Z-Val-Val-MeVal-Pro-OH were prepared by the method disclosed in patent applications DE 4415998 and DE 19527575, the contents of which are incorporated herein by reference.

[0150] a) Synthesis of N,N-dimethyl-2-nitrobenzamide

[0151] To a solution of 2.0 g 2-nitrobenzoic acid and 0.98 g dimethylammonium chloride in dichloromethane at 0° C. were added 2.29 g 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1.62 g N-hydroxy-benzotriazol and 6.05 g N-methyl-morpholine. The resulting mixture was stirred at room temperature overnight. The reaction mixture was then washed sequentially with saturated sodium hydrogen carbonate, a 5% aqueous solution of citric acid and brine. The organic phase was dried over sodium sulfate. After filteration the solvent was removed in vacuo yielding N,N-dimethyl-2-nitrobenzamide (2.13 g).

[0152]¹H-NMR (DMSO, 270 MHz) d=2.7 (s, 3H), 3.0 (s, 3H), 7.5 (d, 1H), 7.7 (dd, 1H), 7.85 (dd, 1H), 8.15 (d, 1H) ppm

[0153] b) Synthesis of N,N-dimethyl-2-aminobenzamide

[0154] Palladium on charcoal (0.54 g, 10% Pd by weight) was added to a solution of 2.1 g N,N-dimethyl-2-nitrobenzamide in 150 mL methanol. The resulting suspension was hydrogenated at room temperature at atmospheric pressure for three hours. After filtration of the catalyst, the solvent was removed in vacuo affording N,N-dimethyl-2-aminobenzamide (1.8 g).

[0155]¹H-NMR (DMSO, 270 MHz) d=2.9 (s, 6H), 5.1 (s, 2H), 6.5 (dd, 1H), 6.65 (d, 1H), 7.95 (d, 1H), 7.0 (dd, 1H) ppm

[0156] c) Synthesis of (2)-(Z-Val-Val-MeVal-Pro-NH)—C₆H₄—CON(CH₃)₂

[0157] To a solution of 2.0 g Z-Val-Val-MeVal-Pro-OH and 0.53 g N,N-dimethyl-2-amino-benzamide in dichloromethane was added 1.66 g bromo-tris-pyrrolidinophosphonium hexafluoro-phosphate (PyBrop) and 0.77 g N-ethyldiisopropylamine at 0° C. The mixture was stirred at room temperature overnight, and then washed sequentially with saturated sodium hydrogen carbonate, a 5% aqueous solution of citric acid, and brine. The organic phase was dried over sodium sulfate. After filtration, the solvent was removed in vacuo. The residue was purified by silica gel chromatography (1:3 dichloromethane:ethyl acetate) to provide (2)-(Z-Val-Val-MeVal-Pro-NH)—C₆H₄—CON(CH₃)₂ (1.8 g).

[0158] FAB-MS 707.0 (M+H+d)

[0159] d) Synthesis of 2-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄—CON(CH₃)₂

[0160] Palladium on charcoal (58 mg, 10% Pd by weight) was added to a solution of 1.8 g 2-(Z-Val-Val-MeVal-Pro-NH)—C ₆H₄—CON(CH₃)₂ in 150 mL methanol. The resulting suspension was hydrogenated at room temperature at atmospheric pressure for three hours, then 1.5 mL of an aqueous formaldehyde solution (37% formaldehyde by weight) and 341 mg of palladium on charcoal were added. The mixture was hydrogenated at room temperature at atmospheric pressure overnight. After filtration over celite the solvent was removed in vacuo to give 1.30 g 2-(Me₂Val-Val-MeVal-Pro-NH)—C ₆H₄—CON(CH₃)₂.

[0161] FAB-MS: 601.0 (M+H⁺)

[0162]¹H-NMR (DMSO, 270 MHz) d=0.7 (s, 6H), 0.8-1.0 (m, 12H), 1.75 (m, 1H), 1.8- 2.2 (m, 6H), 2.2 (s, 6H), 2.6 (d, 1H), 2.8 (s, 3H), 2.9 (s, 3H), 3.05 (s, 3H), 3.55, 3.7 (m, 2H), 4.4 (m, 1H), 4.5 (m, 1H), 5.0 (d, 1H), 7.2 (dd, 1H), 7.25 (d, 1H), 7.4, dd, 1H), 7.6 (dd, 1H), 8.0 (d, 1H), 9.6 (s, 1H)

EXAMPLE 2 Synthesis of (2)-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄—CON(CH₃)(OCH₃) (Compound I-60)

[0163] a) Synthesis of N,O-dimethyl-(2-N-tert.butoxycarbonyl-amino)benzohydroxylamide

[0164] To a solution of 1.5 g 2-N-t-butoxy-carbonyl anthranilic acid and 0.68 g N,O-dimethylhydroxylamine hydrochloride in dichloromethane at 0° C., 1.33 g 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 0.94 g N-hydroxybenzotriazol and 3.20 g N-methylmorpholine were added. The mixture was stirred at room temperature overnight. The reaction mixture was washed sequentially with saturated aqueous sodium hydrogen carbonate, a 5% aqueous solution of citric acid and brine. The organic phase was dried over sodium sulfate. After filtration the solvent was removed in vacuo. Flash chromatography (silica gel, heptane:ethyl acetate 10:1) afforded N,O-dimethyl-(2-N-tert.Butoxycarbonyl-amino)benzohydroxylamide (1.18 g).

[0165]¹H-NMR (CDCl₃, 270 MHz) d=1.5 (s, 9H), 3.4 (s, 3H), 3.6 (s, 3H), 7.0 (dd, 1H), 7.2-7.4 (m, 2H), 8.1 (d, 1H), 8.4 (s, 1H)

[0166] b) Synthesis of N,O-dimethyl-(2-amino)benzohydroxylamide hydrochloride.

[0167] To a solution of 0.5 g N,O-dimethyl-(2-N-tert.butoxycarbonyl-amino)benzohydroxylamide in 15 mL dichloromethane at 0° C. was added 17 mL of a hydrogen chloride solution in ether and the resulting solution was stirred for 2 hours. The solvent was evaporated to give 0.41 g N,O-dimethyl-(2-amino)benzohydroxylamide hydrochloride.

[0168]¹H-NMR (CDCl₃, 270 MHz) d=3.4 (s, 3H), 3.6 (s, 3H), 7.3 (dd, 1H) , 7.5 (dd, 2H) , 7.6 (d, 1H), 7.9 (d, 1H)

[0169] c) Synthesis of (2)-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄—CON(CH₃)(OCH₃)

[0170] To a solution of 0.892 g Me₂Val-Val-MeVal-Pro-OH and 0.234 g triethylamine in 10 mL dichloromethane at 0° C. was added 0.218 g formate. After stirring the resulting mixture for two hours, 0.41 g N,O-dimethyl-(2-amino)benzohydroxylamide hydrochloride and 0.234 g triethylamine were added and the mixture was stirred overnight at room temperature. The reaction mixture was washed sequentially with saturated sodium hydrogen carbonate solution and brine. The organic phase was dried over sodium sulfate. After filtration the solvent was removed in vacuo. The residue was purified by chromatography (silica gel treated with 1% triethylamine, solvent: dichloromethane/3% isopropanol) to provide 0.28 g (2)-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄—CON(CH₃)(OCH₃).

[0171] FAB-MS: 617.5 (M+H⁺)

[0172]¹H-NMR (DMSO, 270 MHz) d=0.7 (s, 6H), 0.8-1.0 (m, 12H), 1.7 (m, 1H), 1.8-2.2 (m, 6H), 2.2 (s, 6H), 2.6 (d, 1H), 3.0 (s, 3H), 3.2 (s, 3H), 3.5 (s, 3H), 3.5, 3.7 (m, 2H), 4.4 (m, 1H), 4.5 (m, 1H) , 5.0 (d, 1H), 7.2 (dd, 1H), 7.3-7.5 (m, 2H), 7.6 (dd, 1H), 8.0 (d, 1H), 9.65 (s, 1H)

EXAMPLE 3 Synthesis of Me₂-Val-Val-MeVal-Pro-[cis-2-aminocyclopentanecarboxylic acid]-NHBn (Compound VII-2)

[0173] d) Synthesis of Racemic Cyclopentane-cis-1,2-dicarboxylic Acid Anhydride

[0174] 8.4 g (44.3 mmol) of commercially available cyclopentane-trans-1,2-dicarboxylic acid was refluxed for 20 h in 75 ml of acetic acid anhydride, then evaporated and the obtained residue distilled in a “Kugelrohr-apparatus” at 1.0 mbar. The fraction boiling at 165° was collected, yielding 5.8 g of the product as an oil.

[0175]¹³C-NMR (400 MHz; DMSO-d₆) d (ppm): 25.3 (C-4), 30.6 (C-3,5), 45.7 (C-1,2), 175.6 (C-6,7).

[0176] b) Synthesis of Racemic Cis-2-carbamoylcyclopentanecarboxylic Acid

[0177] 1.1 g (7.85 mmol) of cyclopentane-cis-1,2-dicarboxylic acid anhydride were added to 8 ml of an aqueous NH₃-solution and stirred until dissolution of the educt. The excess of ammonia was then evaporated, the remaining solution cooled to 0° C. and acidified with conc. HCl. The resulting precipitate was filtered off, washed with cold water and dried, yielding 0.7 g of cis-2-carbamoylcyclopentanecarboxylic acid with a melting point of 132-133° C. (lit.: 126-128° C.).

[0178] c) Synthesis of Racemic Cis-2-aminocyclopentanecarboxylic Acid

[0179] Under stirring at 0° C. 0.41 g (2.6 mmol) of Br₂ were added to an aqueous solution (1.8 mL) of 0.48 g (12 mmol) NaOH. The mixture was cooled again and then 0.34 g (2.16 mmol) of cis-2-carbamoylcyclopentanecarboxylic acid added. After stirring for about 10 minutes again 0.35 g (8.65 mmol) NaOH—dissolved in 1.35 ml of water—were added, and then the whole mixture warmed to 75° C. for about 5 minutes. The mixture then was cooled again, neutralized by addition of conc. HCl, acidified with acetic acid and evaporated to dryness. The residue obtained was extracted five times with refluxing ethanol, and the combined ethanol-fractions evaporated again yielding 1.1 g of a white solid.

[0180] Purification was achieved by filtration of this residue over a column with Dowex 50 ion exchange resin. Therefore the column was washed with a solution of the solid in water, and then the product eluted by treatment with solid was dissolved in water and the column, absorbed on by washing the column with aqueous diluted NH₃. After evaporation of the water the remaining crude product was recristallized from acetone yielding 0.14 g of pure cis-2-aminocyclopentanecarboxylic acid with a melting point of 200-202° C.

[0181] d) Synthesis of Racemic Cis-2-t-butyloxycarbonylaminocyclopentanecarboxylic Acid Benzylamide

[0182] To a solution of 1.5 g (11.6 mmol) of cis-2-aminocyclopentanecarboxylic acid in a mixture of acetonitrile/water 3:1 were added 3.3 g (15.1 mmol) of di^(t)butyldicarbonate, 0.5 g (12.2 mmol) of NaOH dissolved in 12 ml of H₂O and 0.1 g (0.82 mmol) of DMAP. The mixture was stirred at ambient temperature for about 3 days, then diluted with water, extracted with ethylacetate. The combined organic phases were washed with a saturated aqueous NaCl-solution, dried over MgSO₄ and evaporated to dryness leaving 1.3 g of the Boc-protected compound as an oil. A solution of the crude product and 0.65 g (6.1 mmol) benzylamine in a mixture of THF/DMF 10:1 was cooled to −10° C., then were added subsequently 0.9 g (5.86 mmol) of HOBT, 1.12 g (5.86 mmol) of EDC×HCl and 3 ml of NMM. The mixture was stirred for 2 h at −10° C., for 3 h at 0° C. and was then allowed to warm up to room temperature. After evaporation to dryness the remaining residue was dissolved in ethylacetate, washed with aqueous solutions of 5% citric acid, NaHCO₃ and NaCl and dried over MgSO₄. Evaporation yielded 1.3 g of cis-2-t-butyloxycarbonylaminocyclo-pentanecarboxylic acid benzylamide as an oil.

[0183] HPLC (gradient 2): R_(t) 10.5 min.

[0184] (Column: Machery & Nagel Nucleosil C18 PPN, 100×2.1, 5 m/100 A, acetonitrile/H₂O+0.1% TFA; flow: 0.2 ml/min; temp. 40° C.).

[0185]¹H-NMR (270 MHz; DMSO-d₆) d (ppm): 1.35 (s, 9H), 1.35-1.95 (m, 6H), 2.82 (m, 1H), 4.03 (m, 1H), 4.25 (m, 2H), 6.35 (d, NH), 7.1-7.35 (m, 5H), 8.3 (m, 1H).

[0186] e) Synthesis of Racemic Cis-2-aminocyclopentanecarboxylic Acid Benzylamide Hydrochloride

[0187] To a solution of 0.7 g (2.2 mmol) of of cis-2-tert.butyloxycarbonylaminocyclo-pentanecarboxylic acid benzylamide in 30 ml CH₂Cl₂ were added 25 ml of saturated HCl in diethylether; the mixture was then stirred for 2 h at ambient temperature. Evaporation to dryness and coevaporation with toluene yielded 0.6 g of the deprotected amine as hydrochloride salt.

[0188] f) Synthesis of Me₂-Val-Val-MeVal-Pro-[cis-2-aminocyclopentanecarboxylic Acid]-NHBn (Compound VII-2)

[0189] To a solution of 0.86 g (1.9 mmol) of the tetrapeptide Me₂Val-Val-MeVal-Pro-OH and 0.56 g (2.2 mmol) aminocyclo-pentanecarboxylic acid benzylamide hydrochloride in 30 ml of THF/DMF 5:1 were added subsequently at −10° C. 0.29 g (1.9 mmol) of HOBT; 0.37 g (1.9 mmol) of EDC×HCl and 1.2 ml of NMM. The mixture was stirred for another at −10° C., then for 1-2 h at 0° C. and then allowed to warm up to ambient temperature. After evaporation the remaining residue was diluted with ethyl acetate, washed with an aqueous solution of NaCl, dried over MgSO₄ and evaporated again. The remaining crude product (1.2 g) was purified by flash cromatography on silica gel (CH₂Cl₂/CH₃OH) yielding 0.37 g of Me₂Val-Val-MeVal-Pro-[cis-2-aminocyclopentanecarboxylic acid]-NHBn.

[0190] FAB-MS: 655 (M+H⁺).

[0191] The following compounds can be prepared as outlined in Schemes I-III and according to the above examples.

[0192] Table 1:

[0193] A is Me₂Val, B is Val, D is MeVal, E is Pro, F is of Formula II_(F) and the group —C(═O)-G is in position 2 relative to the nitrogen atom. G is of Formula II_(g) or, III_(g) or IV_(g). No. R_(F) R¹ _(F) R² _(F) —C(═O)—G I-1 H H H —NH—CH₃ I-2 H H H —NH—CH₂—C₆H₅ I-3 H H H —NH-isoC₃H₅ I-4 H H H —NH—C₆H₅ I-5 H H H 1,3-Thiazol-2-yl-amide I-6 H 4-OCH₃ 5-OCH₃ —NH—CH₃ I-7 H 3-cycloC₅H₉ H —NH—CH₃ I-8 H H H —NH—C₂H₅ I-9 H H H —NH-nC₃H₇ I-10 H H H —NH-nC₄H₉ I-11 H H H —NH-tertC₄H₉ I-12 H H H —NH-cycloC₃H₅ I-13 H H H —NH-cycloC₄H₇ I-14 H H H —NH-cycloC₅H₉ I-15 H H H —NH-cycloC₆H₁₁ I-16 H H H —NH-cycloC₇H₁₂ I-17 H H H —NH—CH₃—O—CH₃ I-18 H H H —NH—CH₂—CH₂—O—CH₃ I-19 H H H —NH-1-adamantyl I-20 H H H —NH-(4-HO-C₆H₅) I-21 H H H —NH-(2-CF₃—C₆H₄) I-22 H H H —NH-(3-CF₃—C₆H₄) I-23 H H H —NH-(4-CF₃—C₆H₄) I-24 H H H —NH-(2-OCH₃—C₆H₄) I-25 H H H —NH-(3-OCH₃—C₆H₄) I-26 H H H —NH-(4-OCH₃—C₆H₄) I-27 H H H —NH-(2-SCH₃—C₆H₄) I-28 H H H —NH-(3-SCH₃—C₆H₄) I-29 H H H —NH-(4-SCH₃—C₆H₄) I-30 H H H —NH-(2-N(CH₃)₂—C₆H₄) I-31 H H H —NH-(3-N(CH₃)₂—C₆H₄) I-32 H H H —NH-(4-N(CH₃)₂—C₆H₄) I-33 H H H —NH-(4-CN-C₆H₄) I-34 H H H —NH-(4-Cl-C₆H₄) I-35 H H H —NH-(4-Br-C₆H₄] I-36 H H H —NH-(4-F-C₆H₄] I-37 H H H —NH-(4-CH₃—C₆H₄) I-33 H H H —NH-(2-NO₂—C₆H₄) I-39 H H H —NH-(3-NO₂—C₆H₄) I-40 H H H —NH-(4-NO₂—C₆H₄) I-41 H H H —NH-(2,4-OCH₃—C₆H₃) I-42 H H H —NH-(3,4-OCH₃—C₆H₃) I-43 H H H —NH-(3,4,5-OCH₃—C₆H₂) I-44 H H H —NH-(3,4-CH₂OCH₂—C₆H₃) I-45 H H H —NH-(2,3-CH₂OCH₂—C₆H₃) I-46 H H H —NH-2-pyridinyl I-47 H H H —NH-2-furanyl I-48 H H H —NH-2-thienyl I-49 H H H —NH-3-pyridinyl I-50 H H H —NH-3-furanyl I-51 H H H —NH-3-thienyl I-52 H H H —NH-4-pyridinyl I-53 H H H —NH-2-oxazolyl I-54 H H H —NH-3-isoxazolyl I-55 H H H —NH-4-isoxazolyl I-56 H H H —NH-5-isoxazloyl I-57 H H H —NH-2R-(but-2-yl) I-58 H H H —NH-2S-(but-2-yl) I-59 H H H —NH—O—CH₃ I-60 H H H —N(CH₃) (OCH₃) I-61 H H H —N(—(CH₂)3—O—) I-62 H H H —NH—O—CH₂—C₆H₅ I-63 H H H —N(CH₃)(O—CH₂—C₆H₅) I-64 H H H —N(—(CH₂)₂—CH(C₆H₅)—O—) I-65 H H H —NH—O—C₂H₅ I-66 H H H —N(C₂H₅)(OC₂H₅) I-67 H H H —N(CH₂)(OC₂H₅) I-58 H H H —NH—O-isoC₃H₇ I-69 H H H —N(CH₃)(O-isoC₃H₇) I-70 H H H —NH—O—nC₃H₇ I-71 H H H —N(CH₃)(O—nC₃H₇) I-72 H H H —NH—O—nC₄H₉ I-73 H H H —N(CH₂)(O—nC₄H₉) I-74 H H H —NH-O-tertC₄H₉ I-75 H H H —N(CH₃)(O-tertC₄H₉) I-76 H H H —NH—O—C₆H₅ I-77 H H H —N(CH₃)(O—C₆H₅) I-78 H H H —N(CH₃)₂ I-79 H H H —N(CH₂—C₆H₅)₂ I-80 H H H —N(C₂H₅)₂ I-81 H H H —N(isoC₃H₇)₂ I-82 H H H —N(nC₃H₇)₂ I-83 H H H —N(nC₄H₉)₂ I-84 H H H —N(C₆H₅)₂ I-85 H H H —NH—CH₂—CH₂—OH I-86 H H H —NH—(CH₂)₃—OH I-87 H H H —NH(—(CH₂)₂CH(C₆H₅)OH) I-88 H H H —NH—(CH₂)₄—OH I-89 H H H —NH(—CH(CH₃)—CH₂—OH) I-90 H H H —NH(—CH₂—CH(CH₃)—OH) I-91 H H H —NH(CH(CH₃)(CH₂)₂OH) I-92 H H H —NH(—(CH₂)₂CH(CH₃)OH) I-93 H 4-CH₃ H —NH—CH₃ I-94 H 4-CH₃ H —NH—CH₂—C₆H₅ I-95 H 4-CH₃ H —NH—isoC₃H₇ I-96 H 4-CH₃ H —NH—C₆H₅ I-97 H 4-CH₃ H —NH—C₂H₅ I-98 H 4-CH₃ H —NH-nC₃H₇ I-99 H 4-CH₃ H —NH—nC₄H₉ I-100 H 4-CH₃ H —NH-tertC₄H₉ I-101 H 4-CH₃ H —NH-cycloC₃H₅ I-102 H 4-CH₃ H —NH- cycloC₄H₇ I-103 H 4-CH₃ H —NH-cycloC₅H₉ I-104 H 4-CH₃ H —NH-cycloC₆H₁₁ I-105 H 4-CH₃ H —NH-1-adamantyl I-106 H 4-CH₃ H —NH-2R-(but-2-yl) I-107 H 4-CH₃ H —NH-2S-(but-2-yl) I-108 H 4-CH₃ H —NH—O—CH₃ I-109 H 4-CH₃ H —N(CH₃)(OCH₃) I-110 H 4-CH₃ H —N(—(CH₃—O—) I-111 H 4-CH₃ H —N(CH₃)₂ I-112 H 4-CH₃ H —N(CH₂—C₆H₅)₂ I-113 H 4-CH₃ H —N(C₂H₅)₂ I-114 H 4-CH₃ H —N(isoC₃H₇)₂ I-115 H 4-CH₃ H —N(nC₃H₇)₂ I-116 H 4-CH₃ H —N(nC₄H₉)₂ I-117 H 4-CH₃ H —N(C₆H₅)₂ I-118 H 5-CH₃ H —NH—CH₃ I-119 H 5-CH₃ H —NH—CH₂—C₆H₅ I-120 H 5-CH₃ H —NH-isoC₃H₇ I-121 H 5-CH₃ H —NH-C₆H₅ I-122 H 5-CH₃ H —NH-C₂H₅ I-123 H 5-CH₃ H —NH-nC₃H₇ I-124 H 5-CH₃ H —NH-nC₄H₉ I-125 H 5-CH₃ H —NH-tertC₄H₉ I-126 H 5-CH₃ H —NH-cycloC₃H₅ I-127 H 5-CH₃ H —NH-cycloC₄H₇ I-128 H 5-CH₃ H —NH-cycloC₅H₉ I-129 H 5-CH₃ H —NH-cycloC₆H₁₁ I-130 H 5-CH₃ H —NH-1-adamantyl I-131 H 5-CH₃ H —NH-2R-(but-2-yl) I-132 H 5-CH₃ H —NH-2S-(but-2-yl) I-133 H 5-CH₃ H —NH—O—CH₃ I-134 H 5-CH₃ H —N(CH₃)(OCH₃) I-135 H 5-CH₃ H —N(—(CH₃)₃—O—) I-136 H 5-CH₃ H —N(CH₃)₂ I-137 H 5-CH₃ H —N(CH₂—C₆H₅)₂ I-138 H 5-CH₃ H —N(C₂H₅)₂ I-139 H 5-CH₃ H —N(isoC₃H₇)₂ I-140 H 5-CH₃ H —N(nC₃H₇)₂ I-141 H 5-CH₃ H —N(nC₄H₉)₂ I-142 H 5-CH₃ H —N(C₆H₅)₂ I-143 CH₃ H H —NH—CH₃ I-144 CH₃ H H —NH—CH₂—C₆H₅ I-145 CH₃ H H —NH—isoC₃H₇ I-146 CH₃ H H —NH-C₆H₅ I-147 CH₃ H H —NH-C₂H₅ I-148 CH₃ H H —NH-nC₃H₇ I-149 CH₃ H H —NH-nC₄H₉ I-150 CH₃ H H —NH-tertC₄H₉ I-151 CH₃ H H —NH-cycloC₃H₅ I-152 CH₃ H H —NH-cycloC₄H₇ I-153 CH₃ H H —NH-cycloC₅H₉ I-154 CH₃ H H —NH-cycloC₆H₁₁ I-155 CH₃ H H —NH-1-adamantyl I-156 CH₃ H H —NH-2R-(but-2-yl) I-157 CH₃ H H —NH-2S-(but-2-yl) I-158 CH₃ H H —NH—O—CH₃ I-159 CH₃ H H —N(CH₃)(OCH₃) I-160 CH₃ H H —N(—(CH₂)₃—O—) I-161 CH₃ H H —N(CH₃)₂ I-162 CH₃ H H —N(CH₂—C₆H₅)₃ I-163 CH₃ H H —N(C₂H₅)₂ I-164 CH₃ H H —N(isoC₃H₇)₂ I-165 CH₃ H H —N(nC₃H₇)₂ I-155 CH₃ H H —N(nC₄H₉)₂ I-167 CH₃ H H —N(C₆H₅)₂ I-168 H 4-OCH₃ H —NH—CH₃ I-159 H 4-OCH₃ H —NH—CH₂—C₆H₅ I-170 H 4-OCH₃ H —NH-isoC₃H₇ I-171 H 4-OCH₃ H —NH-C₆H₅ I-172 H 4-OCH₃ H —NH-C₂H₅ I-173 H 4-OCH₃ H —NH-nC₄H₇ I-174 H 4-OCH₃ H —NH-nC₅H₉ I-175 H 4-OCH₃ H —NH-tertC₄H₉ I-176 H 4-OCH₃ H —NH-cycloC₃H₅ I-177 H 4-OCH₃ H —NH-cycloC₄H₇ I-178 H 4-OCH₃ H —NH-cycloC₅H₉ I-179 H 4-OCH₃ H —NH-cycloC₆H₁₁ I-180 H 4-OCH₃ H —NH-1-adamantyl I-181 H 4-OCH₃ H —NH-2R-(but-2-yl) I-182 H 4-OCH₃ H —NH-2S-(but-2-yl) I-183 H 4-OCH₃ H —NH—O—CH₃ I-184 H 4-OCH₃ H —N(CH₃)(OCH₃) I-185 H 4-OCH₃ H —N(—(CH₂)₃—O—) I-186 H 4-OCH₃ H —N(CH₃)₂ I-187 H 4-OCH₃ H —N(CH₂—C₆H₅)₂ I-188 H 4-OCH₃ H —N(C₂H₅)₂ I-189 H 4-OCH₃ H —N(isoC₃H₇)₂ I-190 H 4-OCH₃ H —N(nC₃H₇)₂ I-191 H 4-OCH₃ H —N(nC₄H₉)₂ I-192 H 4-CH₃ H —N(C₆H₅)₂ I-193 H 5-OCH₃ H —NH—CH₃ I-194 H 5-OCH₃ H —NH—CH₂—C₆H₅ I-195 H 5-OCH₃ H —NH-isoC₃H₇ I-196 H 5-OCH₃ H —NH—C₆H₅ I-197 H 5-OCH₃ H —NH—C₂H₅ I-198 H 5-OCH₃ H —NH-nC₃H₇ I-199 H 5-OCH₃ H —NH-nC₄H₉ I-200 H 5-OCH₃ H —NH-tertC₄H₉ I-201 H 5-OCH₃ H —NH-cycloC₃H₅ I-202 H 5-OCH₃ H —NH-cycloC₄H₇ I-203 H 5-OCH₃ H —NH-cycloC₅H₉ I-204 H 5-OCH₃ H —NH-cycloC₆H₁₁ I-205 H 5-OCH₃ H —NH-1-adamantyl I-206 H 5-OCH₃ H —NH-2R-(but-2-y1) I-207 H 5-OCH₃ H —NH-2S-(but-2-yl) I-208 H 5-OCH₃ H —NH—O—CH₃ I-209 H 5-OCH₃ H —N(CH₃)(OCH₃) I-210 H 5-OCH₃ H —N(—(CH₂)₃—O—) I-211 H 5-OCH₃ H —N(CH₃)₂ I-212 H 5-OCH₃ H —N(CH₂—C₆H₅)₂ I-213 H 5-OCH₃ H —N(C₂H₅)₂ I-214 H 5-OCH₃ H —N(isoC₃H₇)₂ I-215 H 5-OCH₃ H —N(nC₄H₉)₂ I-216 H 5-OCH₃ H —N(nC₄H₉)₂ I-217 H 5-OCH₃ H —N(C₆H₅)₂

[0194] Table 2:

[0195] A is Me₂Val, B is Val, D is MeVal, E is Pro and F is of Formula II_(f), the group —C(O)-G is in position 3 relative to the nitrogen atom and G is of Formula II_(g), III_(g) or IV_(g). No. R_(F) R¹ _(F) R² _(F) —G II-1 H H H —NH—CH₃ II-2 H H H —NH—CH₂—C₆H₅ II-3 H H H —NH-isoC₃H₅ II-4 H H H —NH—C₆H₅ II-5 H H H 1,3-Thiazol-2-yl-amide II-6 H 4-OCH₃ 5-OCH₃ —NH—CH₃ II-7 H 3-cycloC₅H₉ H —NH—CH₃ II-8 H H H —NH—C₂H₅ II-9 H H H —NH-nC₃H₇ II-10 H H H —NH-nC₄H₉ II-11 H H H —NH-tertC₄H₉ II-12 H H H —NH-cycloC₃H₅ II-13 H H H —NH-cycloC₄H₇ II-14 H H H —NH-cycloC₅H₉ II-15 H H H —NH-cycloC₆H₁₁ II-16 H H H —NH-cycloC₇H₁₂ II-17 H H H —NH—CH₃—O—CH₃ II-18 H H H —NH—CH₂—CH₂—O—CH₃ II-19 H H H —NH-1-adamantyl II-20 H H H —NH-(4-HO-C₆H₅) II-21 H H H —NH-(2-CF₃—C₆H₄) II-22 H H H —NH-(3-CF₃—C₆H₄) II-23 H H H —NH-(4-CF₃—C₆H₄) II-24 H H H —NH-(2-OCH₃—C₆H₄) II-25 H H H —NH-(3-OCH₃—C₆H₄) II-26 H H H —NH-(4-OCH₃—C₆H₄) II-27 H H H —NH-(2-SCH₃—C₆H₄) II-28 H H H —NH-(3-SCH₃—C₆H₄) II-29 H H H —NH-(4-SCH₃—C₆H₄) II-30 H H H —NH-(2-N(CH₃)₂—C₆H₄) II-31 H H H —NH-(3-N(CH₃)₂—C₆H₄) II-32 H H H —NH-(4-N(CH₃)₂—C₆H₄) II-33 H H H —NH-(4-CN-C₆H₄) II-34 H H H —NH-(4-Cl-C₆H₄) II-35 H H H —NH-(4-Br-C₆H₄] II-36 H H H —NH-(4-F-C₆H₄] II-37 H H H —NH-(4-CH₃—C₆H₄) II-33 H H H —NH-(2-NO₂—C₆H₄) II-39 H H H —NH-(3-NO₂—C₆H₄) II-40 H H H —NH-(4-NO₂—C₆H₄) II-41 H H H —NH-(2,4-OCH₃—C₆H₃) II-42 H H H —NH-(3,4-OCH₃—C₆H₃) II-43 H H H —NH-(3,4,5-OCH₃—C₆H₂) II-44 H H H —NH-(3,4-CH₂OCH₂—C₆H₃) II-45 H H H —NH-(2,3-CH₂OCH₂—C₆H₃) II-46 H H H —NH-2-pyridinyl II-47 H H H —NH-2-furanyl II-48 H H H —NH-2-thienyl II-49 H H H —NH-3-pyridinyl II-50 H H H —NH-3-furanyl II-51 H H H —NH-3-thienyl II-52 H H H —NH-4-pyridinyl II-53 H H H —NH-2-oxazolyl II-54 H H H —NH-3-isoxazolyl II-55 H H H —NH-4-isoxazolyl II-56 H H H —NH-5-isoxazloyl II-57 H H H —NH-2R-(but-2-yl) II-58 H H H —NH-2S-(but-2-yl) II-59 H H H —NH—O—CH₃ II-60 H H H —N(CH₃) (OCH₃) II-61 H H H —N(—(CH₂)3—O—) II-62 H H H —NH—O—CH₂—C₆H₅ II-63 H H H —N(CH₃)(O—CH₂—C₆H₅) II-64 H H H —N(—(CH₂)₂—CH(C₆H₅)—O—) II-65 H H H —NH—O—C₂H₅ II-66 H H H —N(C₂H₅)(OC₂H₅) II-67 H H H —N(CH₂)(OC₂H₅) II-68 H H H —NH—O-isoC₃H₇ II-69 H H H —N(CH₃)(O-isoC₃H₇) II-70 H H H —NH—O—nC₃H₇ II-71 H H H —N(CH₃)(O—nC₃H₇) II-72 H H H —NH—O—nC₄H₉ II-73 H H H —N(CH₂)(O—nC₄H₉) II-74 H H H —NH-O-tertC₄H₉ II-75 H H H —N(CH₃)(O-tertC₄H₉) II-76 H H H —NH—O—C₆H₅ II-77 H H H —N(CH₃)(O—C₆H₅) II-78 H H H —N(CH₃)₂ II-79 H H H —N(CH₂—C₆H₅)₂ II-80 H H H —N(C₂H₅)₂ II-81 H H H —N(isoC₃H₇)₂ II-82 H H H —N(nC₃H₇)₂ II-83 H H H —N(nC₄H₉)₂ II-84 H H H —N(C₆H₅)₂ II-85 H H H —NH—CH₂—CH₂—OH II-86 H H H —NH—(CH₂)₃—OH II-87 H H H —NH(—(CH₂)₂CH(C₆H₅)OH) II-88 H H H —NH—(CH₂)₄—OH II-89 H H H —NH(—CH(CH₃)—CH₂—OH) II-90 H H H —NH(—CH₂—CH(CH₃)—OH) II-91 H H H —NH(CH(CH₃)(CH₂)₂OH) II-92 H H H —NH(—(CH₂)₂CH(CH₃)OH) II-93 H 4-CH₃ H —NH—CH₃ II-94 H 4-CH₃ H —NH—CH₂—C₆H₅ II-95 H 4-CH₃ H —NH—isoC₃H₇ II-96 H 4-CH₃ H —NH—C₆H₅ II-97 H 4-CH₃ H —NH—C₂H₅ II-98 H 4-CH₃ H —NH-nC₃H₇ II-99 H 4-CH₃ H —NH—nC₄H₉ II-100 H 4-CH₃ H —NH-tertC₄H₉ II-101 H 4-CH₃ H —NH-cycloC₃H₅ II-102 H 4-CH₃ H —NH- cycloC₄H₇ II-103 H 4-CH₃ H —NH-cycloC₅H₉ II-104 H 4-CH₃ H —NH-cycloC₆H₁₁ II-105 H 4-CH₃ H —NH-1-adamantyl II-106 H 4-CH₃ H —NH-2R-(but-2-yl) II-107 H 4-CH₃ H —NH-2S-(but-2-yl) II-108 H 4-CH₃ H —NH—O—CH₃ II-109 H 4-CH₃ H —N(CH₃)(OCH₃) II-110 H 4-CH₃ H —N(—(CH₃—O—) II-111 H 4-CH₃ H —N(CH₃)₂ II-112 H 4-CH₃ H —N(CH₂—C₆H₅)₂ II-113 H 4-CH₃ H —N(C₂H₅)₂ II-114 H 4-CH₃ H —N(isoC₃H₇)₂ II-115 H 4-CH₃ H —N(nC₃H₇)₂ II-116 H 4-CH₃ H —N(nC₄H₉)₂ II-117 H 4-CH₃ H —N(C₆H₅)₂ II-118 H 5-CH₃ H —NH—CH₃ II-119 H 5-CH₃ H —NH—CH₂—C₆H₅ II-120 H 5-CH₃ H —NH-isoC₃H₇ II-121 H 5-CH₃ H —NH-C₆H₅ II-122 H 5-CH₃ H —NH-C₂H₅ II-123 H 5-CH₃ H —NH-nC₃H₇ II-124 H 5-CH₃ H —NH-nC₄H₉ II-125 H 5-CH₃ H —NH-tertC₄H₉ II-126 H 5-CH₃ H —NH-cycloC₃H₅ II-127 H 5-CH₃ H —NH-cycloC₄H₇ II-128 H 5-CH₃ H —NH-cycloC₅H₉ II-129 H 5-CH₃ H —NH-cycloC₆H₁₁ II-130 H 5-CH₃ H —NH-1-adamantyl II-131 H 5-CH₃ H —NH-2R-(but-2-yl) II-132 H 5-CH₃ H —NH-2S-(but-2-yl) II-133 H 5-CH₃ H —NH—O—CH₃ II-134 H 5-CH₃ H —N(CH₃)(OCH₃) II-135 H 5-CH₃ H —N(—(CH₃)₃—O—) II-136 H 5-CH₃ H —N(CH₃)₂ II-137 H 5-CH₃ H —N(CH₂—C₆H₅)₂ II-138 H 5-CH₃ H —N(C₂H₅)₂ II-139 H 5-CH₃ H —N(isoC₃H₇)₂ II-140 H 5-CH₃ H —N(nC₃H₇)₂ II-141 H 5-CH₃ H —N(nC₄H₉)₂ II-142 H 5-CH₃ H —N(C₆H₅)₂ II-143 CH₃ H H —NH—CH₃ II-144 CH₃ H H —NH—CH₂—C₆H₅ II-145 CH₃ H H —NH—isoC₃H₇ II-146 CH₃ H H —NH-C₆H₅ II-147 CH₃ H H —NH-C₂H₅ II-148 CH₃ H H —NH-nC₃H₇ II-149 CH₃ H H —NH-nC₄H₉ II-150 CH₃ H H —NH-tertC₄H₉ II-151 CH₃ H H —NH-cycloC₃H₅ II-152 CH₃ H H —NH-cycloC₄H₇ II-153 CH₃ H H —NH-cycloC₅H₉ II-154 CH₃ H H —NH-cycloC₆H₁₁ II-155 CH₃ H H —NH-1-adamantyl II-156 CH₃ H H —NH-2R-(but-2-yl) II-157 CH₃ H H —NH-2S-(but-2-yl) II-158 CH₃ H H —NH—O—CH₃ II-159 CH₃ H H —N(CH₃)(OCH₃) II-160 CH₃ H H —N(—(CH₂)₃—O—) II-161 CH₃ H H —N(CH₃)₂ II-162 CH₃ H H —N(CH₂—C₆H₅)₃ II-163 CH₃ H H —N(C₂H₅)₂ II-164 CH₃ H H —N(isoC₃H₇)₂ II-165 CH₃ H H —N(nC₃H₇)₂ II-155 CH₃ H H —N(nC₄H₉)₂ II-167 CH₃ H H —N(C₆H₅)₂ II-168 H 4-OCH₃ H —NH—CH₃ II-159 H 4-OCH₃ H —NH—CH₂—C₆H₅ II-170 H 4-OCH₃ H —NH-isoC₃H₇ II-171 H 4-OCH₃ H —NH-C₆H₅ II-172 H 4-OCH₃ H —NH-C₂H₅ II-173 H 4-OCH₃ H —NH-nC₄H₇ II-174 H 4-OCH₃ H —NH-nC₅H₉ II-175 H 4-OCH₃ H —NH-tertC₄H₉ II-176 H 4-OCH₃ H —NH-cycloC₃H₅ II-177 H 4-OCH₃ H —NH-cycloC₄H₇ II-178 H 4-OCH₃ H —NH-cycloC₅H₉ II-179 H 4-OCH₃ H —NH-cycloC₆H₁₁ II-180 H 4-OCH₃ H —NH-1-adamantyl II-181 H 4-OCH₃ H —NH-2R-(but-2-yl) II-182 H 4-OCH₃ H —NH-2S-(but-2-yl) II-183 H 4-OCH₃ H —NH—O—CH₃ II-184 H 4-OCH₃ H —N(CH₃)(OCH₃) II-185 H 4-OCH₃ H —N(—(CH₂)₃—O—) II-186 H 4-OCH₃ H —N(CH₃)₂ II-187 H 4-OCH₃ H —N(CH₂—C₆H₅)₂ II-188 H 4-OCH₃ H —N(C₂H₅)₂ II-189 H 4-OCH₃ H —N(isoC₃H₇)₂ II-190 H 4-OCH₃ H —N(nC₃H₇)₂ II-191 H 4-OCH₃ H —N(nC₄H₉)₂ II-192 H 4-OCH₃ H —N(C₆H₅)₂ II-193 H 5-OCH₃ H —NH—CH₃ II-194 H 5-OCH₃ H —NH—CH₂—C₆H₅ II-195 H 5-OCH₃ H —NH-isoC₃H₇ II-196 H 5-OCH₃ H —NH—C₆H₅ II-197 H 5-OCH₃ H —NH—C₂H₅ II-198 H 5-OCH₃ H —NH-nC₃H₇ II-199 H 5-OCH₃ H —NH-nC₄H₉ II-200 H 5-OCH₃ H —NH-tertC₄H₉ II-201 H 5-OCH₃ H —NH-cycloC₃H₅ II-202 H 5-OCH₃ H —NH-cycloC₄H₇ II-203 H 5-OCH₃ H —NH-cycloC₅H₉ II-204 H 5-OCH₃ H —NH-cycloC₆H₁₁ II-205 H 5-OCH₃ H —NH-1-adamantyl II-206 H 5-OCH₃ H —NH-2R-(but-2-y1) II-207 H 5-OCH₃ H —NH-2S-(but-2-yl) II-208 H 5-OCH₃ H —NH—O—CH₃ II-209 H 5-OCH₃ H —N(CH₃)(OCH₃) II-210 H 5-OCH₃ H —N(—(CH₂)₃—O—) II-211 H 5-OCH₃ H —N(CH₃)₂ II-212 H 5-OCH₃ H —N(CH₂—C₆H₅)₂ II-213 H 5-OCH₃ H —N(C₂H₅)₂ II-214 H 5-OCH₃ H —N(isoC₃H₇)₂ II-215 H 5-OCH₃ H —N(nC₄H₉)₂ II-216 H 5-OCH₃ H —N(nC₄H₉)₂ II-217 H 5-OCH₃ H —N(C₆H₅)₂

[0196] Table 3:

[0197] A is Me₂Val, B is Val, D is MeVal, E is Pro, F is of Formula II_(f), the substituent —(C═O)-G is in position 4 relative to the nitrogen. G is of Formula II_(g), III_(g) or IV_(g). No. R_(F) R¹ _(F) R² _(F) —G III-1 H H H —NH—CH₃ III-2 H H H —NH—CH₂—C₆H₅ III-3 H H H —NH-isoC₃H₅ III-4 H H H —NH—C₆H₅ III-5 H H H 1,3-Thiazol-2-yl-amide III-6 H 4-OCH₃ 5-OCH₃ —NH—CH₃ III-7 H 3-cycloC₅H₉ H —NH—CH₃ III-8 H H H —NH—C₂H₅ III-9 H H H —NH-nC₃H₇ III-10 H H H —NH-nC₄H₉ III-11 H H H —NH-tertC₄H₉ III-12 H H H —NH-cycloC₃H₅ III-13 H H H —NH-cycloC₄H₇ III-14 H H H —NH-cycloC₅H₉ III-15 H H H —NH-cycloC₆H₁₁ III-16 H H H —NH-cycloC₇H₁₂ III-17 H H H —NH—CH₃—O—CH₃ III-18 H H H —NH—CH₂—CH₂—O—CH₃ III-19 H H H —NH-1-adamantyl III-20 H H H —NH-(4-HO-C₆H₅) III-21 H H H —NH-(2-CF₃—C₆H₄) III-22 H H H —NH-(3-CF₃—C₆H₄) III-23 H H H —NH-(4-CF₃—C₆H₄) III-24 H H H —NH-(2-OCH₃—C₆H₄) III-25 H H H —NH-(3-OCH₃—C₆H₄) III-26 H H H —NH-(4-OCH₃—C₆H₄) III-27 H H H —NH-(2-SCH₃—C₆H₄) III-28 H H H —NH-(3-SCH₃—C₆H₄) III-29 H H H —NH-(4-SCH₃—C₆H₄) III-30 H H H —NH-(2-N(CH₃)₂—C₆H₄) III-31 H H H —NH-(3-N(CH₃)₂—C₆H₄) III-32 H H H —NH-(4-N(CH₃)₂—C₆H₄) III-33 H H H —NH-(4-CN-C₆H₄) III-34 H H H —NH-(4-Cl-C₆H₄) III-35 H H H —NH-(4-Br-C₆H₄] III-36 H H H —NH-(4-F-C₆H₄] III-37 H H H —NH-(4-CH₃—C₆H₄) III-33 H H H —NH-(2-NO₂—C₆H₄) III-39 H H H —NH-(3-NO₂—C₆H₄) III-40 H H H —NH-(4-NO₂—C₆H₄) III-41 H H H —NH-(2,4-OCH₃—C₆H₃) III-42 H H H —NH-(3,4-OCH₃—C₆H₃) III-43 H H H —NH-(3,4,5-OCH₃—C₆H₂) III-44 H H H —NH-(3,4-CH₂OCH₂—C₆H₃) III-45 H H H —NH-(2,3-CH₂OCH₂—C₆H₃) III-46 H H H —NH-2-pyridinyl III-47 H H H —NH-2-furanyl III-48 H H H —NH-2-thienyl III-49 H H H —NH-3-pyridinyl III-50 H H H —NH-3-furanyl III-51 H H H —NH-3-thienyl III-52 H H H —NH-4-pyridinyl III-53 H H H —NH-2-oxazolyl III-54 H H H —NH-3-isoxazolyl III-55 H H H —NH-4-isoxazolyl III-56 H H H —NH-5-isoxazloyl III-57 H H H —NH-2R-(but-2-yl) III-58 H H H —NH-2S-(but-2-yl) III-59 H H H —NH—O—CH₃ III-60 H H H —N(CH₃) (OCH₃) III-61 H H H —N(—(CH₂)3—O—) III-62 H H H —NH—O—CH₂—C₆H₅ III-63 H H H —N(CH₃)(O—CH₂—C₆H₅) III-64 H H H —N(—(CH₂)₂—CH(C₆H₅)—O—) III-65 H H H —NH—O—C₂H₅ III-66 H H H —N(C₂H₅)(OC₂H₅) III-67 H H H —N(CH₂)(OC₂H₅) III-58 H H H —NH—O-isoC₃H₇ III-69 H H H —N(CH₃)(O-isoC₃H₇) III-70 H H H —NH—O—nC₃H₇ III-71 H H H —N(CH₃)(O—nC₃H₇) III-72 H H H —NH—O—nC₄H₉ III-73 H H H —N(CH₂)(O—nC₄H₉) III-74 H H H —NH-O-tertC₄H₉ III-75 H H H —N(CH₃)(O-tertC₄H₉) III-76 H H H —NH—O—C₆H₅ III-77 H H H —N(CH₃)(O—C₆H₅) III-78 H H H —N(CH₃)₂ III-79 H H H —N(CH₂—C₆H₅)₂ III-80 H H H —N(C₂H₅)₂ III-81 H H H —N(isoC₃H₇)₂ III-82 H H H —N(nC₃H₇)₂ III-83 H H H —N(nC₄H₉)₂ III-84 H H H —N(C₆H₅)₂ III-85 H H H —NH—CH₂—CH₂—OH III-86 H H H —NH—(CH₂)₃—OH III-87 H H H —NH(—(CH₂)₂CH(C₆H₅)OH) III-88 H H H —NH—(CH₂)₄—OH III-89 H H H —NH(—CH(CH₃)—CH₂—OH) III-90 H H H —NH(—CH₂—CH(CH₃)—OH) III-91 H H H —NH(CH(CH₃)(CH₂)₂OH) III-92 H H H —NH(—(CH₂)₂CH(CH₃)OH) III-93 H 2-CH₃ H —NH—CH₃ III-94 H 2-CH₃ H —NH—CH₂—C₆H₅ III-95 H 2-CH₃ H —NH—isoC₃H₇ III-96 H 2-CH₃ H —NH—C₆H₅ III-97 H 2-CH₃ H —NH—C₂H₅ III-98 H 2-CH₃ H —NH-nC₃H₇ III-99 H 2-CH₃ H —NH—nC₄H₉ III-100 H 2-CH₃ H —NH-tertC₄H₉ III-101 H 2-CH₃ H —NH-cycloC₃H₅ III-102 H 2-CH₃ H —NH- cycloC₄H₇ III-103 H 2-CH₃ H —NH-cycloC₅H₉ III-104 H 2-CH₃ H —NH-cycloC₆H₁₁ III-105 H 2-CH₃ H —NH-1-adamantyl III-106 H 2-CH₃ H —NH-2R-(but-2-yl) III-107 H 2-CH₃ H —NH-2S-(but-2-yl) III-108 H 2-CH₃ H —NH—O—CH₃ III-109 H 2-CH₃ H —N(CH₃)(OCH₃) III-110 H 2-CH₃ H —N(—(CH₃—O—) III-111 H 2-CH₃ H —N(CH₃)₂ III-112 H 2-CH₃ H —N(CH₂—C₆H₅)₂ III-113 H 2-CH₃ H —N(C₂H₅)₂ III-114 H 2-CH₃ H —N(isoC₃H₇)₂ III-115 H 2-CH₃ H —N(nC₃H₇)₂ III-116 H 2-CH₃ H —N(nC₄H₉)₂ III-117 H 2-CH₃ H —N(C₆H₅)₂ III-118 H 3-CH₃ H —NH—CH₃ III-119 H 3-CH₃ H —NH—CH₂—C₆H₅ III-120 H 3-CH₃ H —NH-isoC₃H₇ III-121 H 3-CH₃ H —NH-C₆H₅ III-122 H 3-CH₃ H —NH-C₂H₅ III-123 H 3-CH₃ H —NH-nC₃H₇ III-124 H 3-CH₃ H —NH-nC₄H₉ III-125 H 3-CH₃ H —NH-tertC₄H₉ III-126 H 3-CH₃ H —NH-cycloC₃H₅ III-127 H 3-CH₃ H —NH-cycloC₄H₇ III-128 H 3-CH₃ H —NH-cycloC₅H₉ III-129 H 3-CH₃ H —NH-cycloC₆H₁₁ III-130 H 3-CH₃ H —NH-1-adamantyl III-131 H 3-CH₃ H —NH-2R-(but-2-yl) III-132 H 3-CH₃ H —NH-2S-(but-2-yl) III-133 H 3-CH₃ H —NH—O—CH₃ III-134 H 3-CH₃ H —N(CH₃)(OCH₃) III-135 H 3-CH₃ H —N(—(CH₃)₃—O—) III-136 H 3-CH₃ H —N(CH₃)₂ III-137 H 3-CH₃ H —N(CH₂—C₆H₅)₂ III-138 H 3-CH₃ H —N(C₂H₅)₂ III-139 H 3-CH₃ H —N(isoC₃H₇)₂ III-140 H 3-CH₃ H —N(nC₃H₇)₂ III-141 H 3-CH₃ H —N(nC₄H₉)₂ III-142 H 3-CH₃ H —N(C₆H₅)₂ III-143 CH₃ H H —NH—CH₃ III-144 CH₃ H H —NH—CH₂—C₆H₅ III-145 CH₃ H H —NH—isoC₃H₇ III-146 CH₃ H H —NH-C₆H₅ III-147 CH₃ H H —NH-C₂H₅ III-148 CH₃ H H —NH-nC₃H₇ III-149 CH₃ H H —NH-nC₄H₉ III-150 CH₃ H H —NH-tertC₄H₉ III-151 CH₃ H H —NH-cycloC₃H₅ III-152 CH₃ H H —NH-cycloC₄H₇ III-153 CH₃ H H —NH-cycloC₅H₉ III-154 CH₃ H H —NH-cycloC₆H₁₁ III-155 CH₃ H H —NH-1-adamantyl III-156 CH₃ H H —NH-2R-(but-2-yl) III-157 CH₃ H H —NH-2S-(but-2-yl) III-158 CH₃ H H —NH—O—CH₃ III-159 CH₃ H H —N(CH₃)(OCH₃) III-160 CH₃ H H —N(—(CH₂)₃—O—) III-161 CH₃ H H —N(CH₃)₂ III-162 CH₃ H H —N(CH₂—C₆H₅)₃ III-163 CH₃ H H —N(C₂H₅)₂ III-164 CH₃ H H —N(isoC₃H₇)₂ III-165 CH₃ H H —N(nC₃H₇)₂ III-166 CH₃ H H —N(nC₄H₉)₂ III-167 CH₃ H H —N(C₆H₅)₂ III-168 H 2-OCH₃ H —NH—CH₃ III-169 H 2-OCH₃ H —NH—CH₂—C₆H₅ III-170 H 2-OCH₃ H —NH-isoC₃H₇ III-171 H 2-OCH₃ H —NH-C₆H₅ III-172 H 2-OCH₃ H —NH-C₂H₅ III-173 H 2-OCH₃ H —NH-nC₄H₇ III-174 H 2-OCH₃ H —NH-nC₅H₉ III-175 H 2-OCH₃ H —NH-tertC₄H₉ III-176 H 2-OCH₃ H —NH-cycloC₃H₅ III-177 H 2-OCH₃ H —NH-cycloC₄H₇ III-178 H 2-OCH₃ H —NH-cycloC₅H₉ III-179 H 2-OCH₃ H —NH-cycloC₆H₁₁ III-180 H 2-OCH₃ H —NH-1-adamantyl III-181 H 2-OCH₃ H —NH-2R-(but-2-yl) III-182 H 2-OCH₃ H —NH-2S-(but-2-yl) III-183 H 2-OCH₃ H —NH—O—CH₃ III-184 H 2-OCH₃ H —N(CH₃)(OCH₃) III-185 H 2-OCH₃ H —N(—(CH₂)₃—O—) III-186 H 2-OCH₃ H —N(CH₃)₂ III-187 H 2-OCH₃ H —N(CH₂—C₆H₅)₂ III-188 H 2-OCH₃ H —N(C₂H₅)₂ III-189 H 2-OCH₃ H —N(isoC₃H₇)₂ III-190 H 2-OCH₃ H —N(nC₃H₇)₂ III-191 H 2-OCH₃ H —N(nC₄H₉)₂ III-192 H 2-OCH₃ H —N(C₆H₅)₂ III-193 H 3-OCH₃ H —NH—CH₃ III-194 H 3-OCH₃ H —NH—CH₂—C₆H₅ III-195 H 3-OCH₃ H —NH-isoC₃H₇ III-196 H 3-OCH₃ H —NH—C₆H₅ III-197 H 3-OCH₃ H —NH—C₂H₅ III-198 H 3-OCH₃ H —NH-nC₃H₇ III-199 H 3-OCH₃ H —NH-nC₄H₉ III-200 H 3-OCH₃ H —NH-tertC₄H₉ III-201 H 3-OCH₃ H —NH-cycloC₃H₅ III-202 H 3-OCH₃ H —NH-cycloC₄H₇ III-203 H 3-OCH₃ H —NH-cycloC₅H₉ III-204 H 3-OCH₃ H —NH-cycloC₆H₁₁ III-205 H 3-OCH₃ H —NH-1-adamantyl III-206 H 3-OCH₃ H —NH-2R-(but-2-y1) III-207 H 3-OCH₃ H —NH-2S-(but-2-yl) III-208 H 3-OCH₃ H —NH—O—CH₃ III-209 H 3-OCH₃ H —N(CH₃)(OCH₃) III-210 H 3-OCH₃ H —N(—(CH₂)₃—O—) III-211 H 3-OCH₃ H —N(CH₃)₂ III-212 H 3-OCH₃ H —N(CH₂—C₆H₅)₂ III-213 H 3-OCH₃ H —N(C₂H₅)₂ III-214 H 3-OCH₃ H —N(isoC₃H₇)₂ III-215 H 3-OCH₃ H —N(nC₄H₉)₂ III-216 H 3-OCH₃ H —N(nC₄H₉)₂ III-217 H 3-OCH₃ H —N(C₆H₅)₂

[0198] Table 4:

[0199] A is Me₂Val, B is Val, D is MeVal, E is Pro and F is of Formula II_(f), the substituent —(C═O)-G is in position 2 relative to the nitrogen. G is of Formula V_(g), VI_(g), VII_(g), VIII_(g) or IX_(g). No. R_(F) R¹F R²F -G IV-1 H H H —CH₃ IV-2 H H H —C₂H₅ IV-3 H H H -nC₃H₇ IV-4 H H H -isoC₃H₇ IV-5 H H H -nC₄H₉ IV-6 H H H -tertC₄H₉ IV-7 H H H -cycloC₃H₅ IV-8 H H H -cycloC₄H₇ IV-9 H H H -cycloC₅H₉ IV-10 H H H -cycloC₆H₁₁ IV-11 H H H -cycloC₇H₁₂ IV-12 H H H —CH₂—O—CH₃ IV-13 H H H —CH₂—CH₂—O—CH₃ IV-14 H H H —CH₂—C₆H₅ IV-15 H H H —C₆H₅ IV-16 H H H -(4-HO—C₆H₅) IV-17 H H H -(2-CF₃—C₆H₄) IV-18 H H H -(3-CF₃—C₆H₄) IV-19 H H H -(4-CF₃—C₆H₄) IV-20 H H H -(2-OCH₃—C₆H₄) IV-21 H H H -(3-OCH₃—C₆H₄) IV-22 H H H -(4-OCH₃—C₆H₄) IV-23 H H H -(2-SCH₃—C₆H₄) IV-24 H H H -(3-SCH₃—C₆H₄) IV-25 H H H -(4-SCH₃—C₆H₄) IV-26 H H H -(2-N(CH₃)₂—C₆H₄) IV-27 H H H -(3-N(CH₃)₂—C₆H₄) IV-28 H H H -(4-N(CH₃)₂—C₆H₄) IV-29 H H H -(4-CN—C₆H₄) IV-30 H H H -(4-Cl—C₆H₄) IV-31 H H H -(4-Br—C₆H₄] IV-32 H H H -(4-F—C₆H₄] IV-33 H H H -(4-CH₃—C₆H₄) IV-34 H H H -(2-NO₂—C₆H₄) IV-35 H H H -(3-NO₂—C₆H₄) IV-36 H H H -(4-NO₂—C₆H₄] IV-37 H H H -(2,4-OCH₃—C₆H₃) IV-38 H H H -(3,4-OCH₃—C₆H₃) IV-39 H H H -(3,4,5-OCH₃—C₆H₂) IV-40 H H H -(3,4-CH₂OCH₂—C₆H₃) IV-41 H H H -(2,3-CH₂OCH₂—C₆H₃) IV-42 H H H -2-pyridinyl IV-43 H H H -2-furanyl IV-44 H H H -2-thienyl IV-45 H H H -3-pyridinyl IV-46 H H H -3-furanyl IV-47 H H H -3-thienyl IV-48 H H H -4-pyridinyl IV-49 H H H -2-thiazolyl IV-50 H H H -2-oxazolyl IV-51 H H H -3-isoxazolyl IV-52 H H H -4-isoxazolyl IV-53 H H H -5-isoxazolyl IV-54 H H H —CF₃ IV-55 H H H —C₂F₅ IV-56 H H H —CH₃ IV-57 H H H —C₂H₅ IV-58 H H H -nC₃H₇ IV-59 H H H -tertC₄H₉ IV-60 H H H —CH₂—C₆H₅ IV-61 H H H —C₆H₅ IV-62 H H H —CH₂—COOCH₃ IV-63 H H H —CH₂—COOC₂H₅ IV-64 H H H —CF₂—COOCH₃ IV-65 H H H —CF₂—COOC₂H₅ IV-66 H H H —CH₂—CONH₂ IV-67 H H H —CH₂—CONHCH₃ IV-68 H H H —CH₂—CON(CH₃)₂ IV-69 H H H —CH₂—CONH—CH₂—C₆H₅ IV-70 H H H —CH₂—CONH—C₆H₅ IV-71 H H H —CH₂—CONH(CH₂—C₆H₅)₂ IV-72 H H H —CH₂—CON(—CH₂—CH₂— CH₂—CH₂—) IV-73 H H H —CH₂—CON(—CH₂—CH₂— CH₂—CH₂—CH₂) IV-74 H H H —CH₂—CH₂—COOCH₃ IV-75 H H H —CH₂—CH₂—COOC₂H₅ IV-76 H H H —CH₂—CH₂—CONH₂ IV-77 H H H —CH₂—CH₂—CONHCH₃ IV-78 H H H —CH₂—CH₂—CON(CH₃)₂ IV-79 H H H —CH₂—CH₂—CONH—CH₂—C₆H₅ IV-80 H H H —CH₂—CH₂—CONH—C₆H₅ IV-81 H H H —CH₂—CH₂—CONH(CH₂—C₆H₅)₂ IV-82 H H H —CH₂—CH₂—CON(—CH₂—CH₂— CH₂—CH₂—) IV-83 H H H —CH₂—CH₂—CON(—CH₂— (CH₂)₃—CH₂) IV-84 H H H —CH₂—COCH₃ IV-85 H H H —CH₂—CH₂—COCH₃ IV-86 H H H —CH₂—COC₂H₅ IV-87 H H H —CH₂—CH₂—COC₂H₅ IV-88 H H H —CH₂—CO—C₆H₅ IV-89 H H H —CH₂—CH₂—CO—C₆H₅ IV-90 H H H —CH₂—CO—CH₂—C₆H₅ IV-91 H H H —CH₂—CH₂—CO—CH₂—C₆H₅ IV-92 H H H —CH₂—SOC₆H₅ IV-93 H H H —CH₂—SOCH₃ IV-94 H H H —CH₂SO(4-CH₃—C₆H₄) IV-95 H H H —CH₂—SO₂C₆H₅ IV-96 H H H —CH₂—SO₂CH₃ IV-97 H H H —CH₂—SO₂(4-CH₃—C₆H₄) IV-98 H H H —CH₂—CH₂—SOC₆H₅ IV-99 H H H —CH₂—CH₂—SOCH₃ IV-100 H H H —CH₂—CH₂—SO(4-CH₃—C₆H₄) IV-101 H H H —CH₂—CH₂—SO₂C₆H₅ IV-102 H H H —CH₂—CH₂—SO₂CH₃ IV-103 H H H —CH₂—CH₂—SO₃(4-CH₃—C₆H₄) IV-104 CH₃ H H —CH₃ IV-105 CH₃ H H —C₂H₅ IV-106 CH₃ H H -nC₃H₇ IV-107 CH₃ H H -isoC₃H₇ IV-108 CH₃ H H -nC₄H₉ IV-109 CH₃ H H -tertC₄H₉ IV-110 CH₃ H H -cycloC₃H₅ IV-111 CH₃ H H -cycloC₄H₇ IV-112 CH₃ H H -cycloC₅H₉ IV-113 CH₃ H H -cycloC₆H₁₁ IV-114 CH₃ H H -cycloC₇H₁₂ IV-115 CH₃ H H —CH₂—O—CH₃ IV-116 CH₃ H H —CH₂—CH₃—O—CH₃ IV-117 CH₃ H H —CH₂—C₆H₅ IV-118 CH₃ H H —C₆H₅ IV-119 CH₃ H H -(4-HO-C₆H₅) IV-120 CH₃ H H -(2-CF₃—C₆H₄) IV-121 CH₃ H H -(3-CF₃—C₆H₄) IV-122 CH₃ H H -(4-CF₃—C₆H₄) IV-123 CH₃ H H -(2-OCH₃—C₆H₄) IV-124 CH₃ H H -(3-OCH₃—C₆H₄) IV-125 CH₃ H H -(4-OCH₃—C₆H₄) IV-126 CH₃ H H -(2-SCH₃—C₆H₄) IV-127 CH₃ H H -(3-SCH₃—C₆H₄) IV-128 CH₃ H H -(4-SCH₃—C₆H₄) IV-129 CH₃ H H -(2-N(CH₃)₂—C₆H₄) IV-130 CH₃ H H -(3-N(CH₃)₂—C₆H₄) IV-131 CH₃ H H -(4-N(CH₃)₂—C₆H₄) IV-132 CH₃ H H -(4-CN-C₆H₄) IV-133 CH₃ H H -(4-Cl—C₆H₄) IV-134 CH₃ H H -(4-Br—C₆H₄] IV-135 CH₃ H H -(4-F—C₆H₄] IV-136 CH₃ H H -(4-CH₃—C₆H₄) IV-137 CH₃ H H -(2-NO₂—C₆H₄) IV-138 CH₃ H H -(3-NO₂—C₆H₄) IV-139 CH₃ H H -(4-NO₂—C₆H₄] IV-140 CH₃ H H -(2,4-OCH₃—C₆H₃) IV-141 CH₃ H H -(3,4-OCH₃—C₆H₃) IV-142 CH₃ H H -(3,4,5-OCH₃—C₆H₂) IV-143 CH₃ H H -(3,4-CH₂OCH₂—C₆H₃) IV-144 CH₃ H H -(2,3-CH₂OCH₂—C₆H₃) IV-145 CH₃ H H -2-pyridinyl IV-146 CH₃ H H -2-furanyl IV-147 CH₃ H H -2-thienyl IV-148 CH₃ H H -3-pyridinyl IV-149 CH₃ H H -3-furanyl IV-150 CH₃ H H -3-thienyl IV-151 CH₃ H H -4-pyridinyl IV-152 CH₃ H H -2-thiazolyl IV-153 CH₃ H H -2-oxazolyl IV-154 CH₃ H H -3-isoxazolyl IV-155 CH₃ H H -4-isoxazolyl IV-156 CH₃ H H -5-isoxazoyl IV-157 CH₃ H H —CF₃ IV-158 CH₃ H H —C₂F₅ IV-159 CH₃ H H —CH₃ IV-160 CH₃ H H —C₂H₅ IV-161 CH₃ H H -nC₃H₇ IV-162 CH₃ H H -tertC₄H₉ IV-163 CH₃ H H —CH₂—C₆H₅ IV-164 CH₃ H H —C₆H₅ IV-165 CH₃ H H —CH₂—COOCH₃ IV-166 CH₃ H H —CH₂—COOC₂H₅ IV-167 CH₃ H H —CF₂—COOCH₃ IV-168 CH₃ H H —CF₂—COOC₂H₅ IV-169 CH₃ H H —CH₂—CONH₂ IV-170 CH₃ H H —CH₂—CONHCH₃ IV-171 CH₃ H H —CH₂—CON(CH₃)₂ IV-172 CH₃ H H —CH₂—CONH—CH₂—C₆H₅ IV-173 CH₃ H H —CH₂—CONH—C₆H₅ IV-174 CH₃ H H —CH₂—CONH(CH₂—C₆H₅)₂ IV-175 CH₃ H H —CH₂—CON(—CH₂—CH₂— CH₂—CH₂—) IV-176 CH₃ H H —CH₂—CON(—CH₂—CH₂—CH₂— CH₂—CH₂) IV-177 CH₃ H H —CH₂—CH₂—COOCH₃ IV-178 CH₃ H H —CH₂—CH₂—COOC₂H₅ IV-179 CH₃ H H —CH₂—CH₂—CONH₂ IV-180 CH₃ H H —CH₂—CH₂—CONHCH₃ IV-181 CH₃ H H —CH₂—CH₂—CON(CH₃)₂ IV-182 CH₃ H H —CH₂—CH₂—CONH—CH₂—C₆H₅ IV-183 CH₃ H H —CH₂—CH₂—CONH—C₆H₅ IV-184 CH₃ H H —CH₂—CH₂—CONH(CH₂—C₆H₅)₂ IV-185 CH₃ H H —CH₂—CH₂—CON(— CH₂—CH₂—CH₂—CH₂—) IV-186 CH₃ H H —CH₂—CH₂—CON(—CH₂— (CH₂)₃—CH₂) IV-187 CH₃ H H —CH₂—COCH₃ IV-188 CH₃ H H —CH₂—CH₂—COCH₃ IV-189 CH₃ H H —CH₂—COC₂H₅ IV-190 CH₃ H H —CH₂—CH₂—COC₂H₅ IV-191 CH₃ H H —CH₂—CO—C₆H₅ IV-192 CH₃ H H —CH₂—CH₂—CO—C₆H₅ IV-193 CH₃ H H —CH₂—CO—CH₂—C₆H₅ IV-194 CH₃ H H —CH₂—CH₂—CO—CH₂—C₆H₅ IV-195 CH₃ H H —CH₂—SOC₆H₅ IV-196 CH₃ H H —CH₂—SOCH₃ IV-197 CH₃ H H —CH₂—SO(4-CH₃—C₆H₄) IV-198 CH₃ H H —CH₂—SO₂C₆H₅ IV-199 CH₃ H H —CH₂—SO₂CH₃ IV-200 CH₃ H H —CH₂—SO₂(4-CH₃—C₆H₄) IV-201 CH₃ H H —CH₂—CH₂—SOC₆H₅ IV-202 CH₃ H H —CH₂—CH₂—SOCH₃ IV-203 CH₃ H H —CH₂—CH₂—SO(4-CH₃—C₆H₄) IV-204 CH₃ H H —CH₂—CH₂—SO₂C₆H₅ IV-205 CH₃ H H —CH₂—CH₂—SO₂CH₃ IV-206 CH₃ H H —CH₂—CH₂—SO₂(4-CH₃—C₆H₄)

[0200] Table 5:

[0201] A is Me₂Val, B is Val, D is MeVal, E is Pro and F is of Formula II_(f), the substituent —(C═O)-G is in position 3 relative to the nitrogen. G is of Formula V_(g), VI_(g), VII_(g), VIII_(g) or IX_(g). No. R_(F) R¹F R²F -G V-1 H H H —CH₃ V-2 H H H —C₂H₅ V-3 H H H -nC₃H₇ V-4 H H H -isoC₃H₇ V-5 H H H -nC₄H₉ V-6 H H H -tertC₄H₉ V-7 H H H -cycloC₃H₅ V-8 H H H -cycloC₄H₇ V-9 H H H -cycloC₅H₉ V-10 H H H -cycloC₆H₁₁ V-11 H H H -cycloC₇H₁₂ V-12 H H H —CH₂—O—CH₃ V-13 H H H —CH₂—CH₂—O—CH₃ V-14 H H H —CH₂—C₆H₅ V-15 H H H —C₆H₅ V-16 H H H -(4-HO—C₆H₅) V-17 H H H -(2-CF₃—C₆H₄) V-18 H H H -(3-CF₃—C₆H₄) V-19 H H H -(4-CF₃—C₆H₄) V-20 H H H -(2-OCH₃—C₆H₄) V-21 H H H -(3-OCH₃—C₆H₄) V-22 H H H -(4-OCH₃—C₆H₄) V-23 H H H -(2-SCH₃—C₆H₄) V-24 H H H -(3-SCH₃—C₆H₄) V-25 H H H -(4-SCH₃—C₆H₄) V-26 H H H -(2-N(CH₃)₂—C₆H₄) V-27 H H H -(3-N(CH₃)₂—C₆H₄) V-28 H H H -(4-N(CH₃)₂—C₆H₄) V-29 H H H -(4-CN—C₆H₄) V-30 H H H -(4-Cl—C₆H₄) V-31 H H H -(4-Br—C₆H₄] V-32 H H H -(4-F—C₆H₄] V-33 H H H -(4-CH₃—C₆H₄) V-34 H H H -(2-NO₂—C₆H₄) V-35 H H H -(3-NO₂—C₆H₄) V-36 H H H -(4-NO₂—C₆H₄] V-37 H H H -(2,4-OCH₃—C₆H₃) V-38 H H H -(3,4-OCH₃—C₆H₃) V-39 H H H -(3,4,5-OCH₃—C₆H₂) V-40 H H H -(3,4-CH₂OCH₂—C₆H₃) V-41 H H H -(2,3-CH₂OCH₂—C₆H₃) V-42 H H H -2-pyridinyl V-43 H H H -2-furanyl V-44 H H H -2-thienyl V-45 H H H -3-pyridinyl V-46 H H H -3-furanyl V-47 H H H -3-thienyl V-48 H H H -4-pyridinyl V-49 H H H -2-thiazolyl V-50 H H H -2-oxazolyl V-51 H H H -3-isoxazolyl V-52 H H H -4-isoxazolyl V-53 H H H -5-isoxazolyl V-54 H H H —CF₃ V-55 H H H —C₂F₅ V-56 H H H —CH₃ V-57 H H H —C₂H₅ V-58 H H H -nC₃H₇ V-59 H H H -tertC₄H₉ V-60 H H H —CH₂—C₆H₅ V-61 H H H —C₆H₅ V-62 H H H —CH₂—COOCH₃ V-63 H H H —CH₂—COOC₂H₅ V-64 H H H —CF₂—COOCH₃ V-65 H H H —CF₂—COOC₂H₅ V-66 H H H —CH₂—CONH₂ V-67 H H H —CH₂—CONHCH₃ V-68 H H H —CH₂—CON(CH₃)₂ V-69 H H H —CH₂—CONH—CH₂—C₆H₅ V-70 H H H —CH₂—CONH—C₆H₅ V-71 H H H —CH₂—CONH(CH₂—C₆H₅)₂ V-72 H H H —CH₂—CON(—CH₂—CH₂— CH₂—CH₂—) V-73 H H H —CH₂—CON(—CH₂—CH₂— CH₂—CH₂—CH₂) V-74 H H H —CH₂—CH₂—COOCH₃ V-75 H H H —CH₂—CH₂—COOC₂H₅ V-76 H H H —CH₂—CH₂—CONH₂ V-77 H H H —CH₂—CH₂—CONHCH₃ V-78 H H H —CH₂—CH₂—CON(CH₃)₂ V-79 H H H —CH₂—CH₂—CONH—CH₂—C₆H₅ V-80 H H H —CH₂—CH₂—CONH—C₆H₅ V-81 H H H —CH₂—CH₂—CONH(CH₂—C₆H₅)₂ V-82 H H H —CH₂—CH₂—CON(—CH₂—CH₂— CH₂—CH₂—) V-83 H H H —CH₂—CH₂—CON(—CH₂— (CH₂)₃—CH₂) V-84 H H H —CH₂—COCH₃ V-85 H H H —CH₂—CH₂—COCH₃ V-86 H H H —CH₂—COC₂H₅ V-87 H H H —CH₂—CH₂—COC₂H₅ V-88 H H H —CH₂—CO—C₆H₅ V-89 H H H —CH₂—CH₂—CO—C₆H₅ V-90 H H H —CH₂—CO—CH₂—C₆H₅ V-91 H H H —CH₂—CH₂—CO—CH₂—C₆H₅ V-92 H H H —CH₂—SOC₆H₅ V-93 H H H —CH₂—SOCH₃ V-94 H H H —CH₂SO(4-CH₃—C₆H₄) V-95 H H H —CH₂—SO₂C₆H₅ V-96 H H H —CH₂—SO₂CH₃ V-97 H H H —CH₂—SO₂(4-CH₃—C₆H₄) V-98 H H H —CH₂—CH₂—SOC₆H₅ V-99 H H H —CH₂—CH₂—SOCH₃ V-100 H H H —CH₂—CH₂—SO(4-CH₃—C₆H₄) V-101 H H H —CH₂—CH₂—SO₂C₆H₅ V-102 H H H —CH₂—CH₂—SO₂CH₃ V-103 H H H —CH₂—CH₂—SO₃(4-CH₃—C₆H₄) V-104 CH₃ H H —CH₃ V-105 CH₃ H H —C₂H₅ V-106 CH₃ H H -nC₃H₇ V-107 CH₃ H H -isoC₃H₇ V-108 CH₃ H H -nC₄H₉ V-109 CH₃ H H -tertC₄H₉ V-110 CH₃ H H -cycloC₃H₅ V-111 CH₃ H H -cycloC₄H₇ V-112 CH₃ H H -cycloC₅H₉ V-113 CH₃ H H -cycloC₆H₁₁ V-114 CH₃ H H -cycloC₇H₁₂ V-115 CH₃ H H —CH₂—O—CH₃ V-116 CH₃ H H —CH₂—CH₃—O—CH₃ V-117 CH₃ H H —CH₂—C₆H₅ V-118 CH₃ H H —C₆H₅ V-119 CH₃ H H -(4-HO-C₆H₅) V-120 CH₃ H H -(2-CF₃—C₆H₄) V-121 CH₃ H H -(3-CF₃—C₆H₄) V-122 CH₃ H H -(4-CF₃—C₆H₄) V-123 CH₃ H H -(2-OCH₃—C₆H₄) V-124 CH₃ H H -(3-OCH₃—C₆H₄) V-125 CH₃ H H -(4-OCH₃—C₆H₄) V-126 CH₃ H H -(2-SCH₃—C₆H₄) V-127 CH₃ H H -(3-SCH₃—C₆H₄) V-128 CH₃ H H -(4-SCH₃—C₆H₄) V-129 CH₃ H H -(2-N(CH₃)₂—C₆H₄) V-130 CH₃ H H -(3-N(CH₃)₂—C₆H₄) V-131 CH₃ H H -(4-N(CH₃)₂—C₆H₄) V-132 CH₃ H H -(4-CN-C₆H₄) V-133 CH₃ H H -(4-Cl—C₆H₄) V-134 CH₃ H H -(4-Br—C₆H₄] V-135 CH₃ H H -(4-F—C₆H₄] V-136 CH₃ H H -(4-CH₃—C₆H₄) V-137 CH₃ H H -(2-NO₂—C₆H₄) V-138 CH₃ H H -(3-NO₂—C₆H₄) V-139 CH₃ H H -(4-NO₂—C₆H₄] V-140 CH₃ H H -(2,4-OCH₃—C₆H₃) V-141 CH₃ H H -(3,4-OCH₃—C₆H₃) V-142 CH₃ H H -(3,4,5-OCH₃—C₆H₂) V-143 CH₃ H H -(3,4-CH₂OCH₂—C₆H₃) V-144 CH₃ H H -(2,3-CH₂OCH₂—C₆H₃) V-145 CH₃ H H -2-pyridinyl V-146 CH₃ H H -2-furanyl V-147 CH₃ H H -2-thienyl V-148 CH₃ H H -3-pyridinyl V-149 CH₃ H H -3-furanyl V-150 CH₃ H H -3-thienyl V-151 CH₃ H H -4-pyridinyl V-152 CH₃ H H -2-thiazolyl V-153 CH₃ H H -2-oxazolyl V-154 CH₃ H H -3-isoxazolyl V-155 CH₃ H H -4-isoxazolyl V-156 CH₃ H H -5-isoxazoyl V-157 CH₃ H H —CF₃ V-158 CH₃ H H —C₂F₅ V-159 CH₃ H H —CH₃ V-160 CH₃ H H —C₂H₅ V-161 CH₃ H H -nC₃H₇ V-162 CH₃ H H -tertC₄H₉ V-163 CH₃ H H —CH₂—C₆H₅ V-164 CH₃ H H —C₆H₅ V-165 CH₃ H H —CH₂—COOCH₃ V-166 CH₃ H H —CH₂—COOC₂H₅ V-167 CH₃ H H —CF₂—COOCH₃ V-168 CH₃ H H —CF₂—COOC₂H₅ V-169 CH₃ H H —CH₂—CONH₂ V-170 CH₃ H H —CH₂—CONHCH₃ V-171 CH₃ H H —CH₂—CON(CH₃)₂ V-172 CH₃ H H —CH₂—CONH—CH₂—C₆H₅ V-173 CH₃ H H —CH₂—CONH—C₆H₅ V-174 CH₃ H H —CH₂—CONH(CH₂—C₆H₅)₂ V-175 CH₃ H H —CH₂—CON(—CH₂—CH₂— CH₂—CH₂—) V-176 CH₃ H H —CH₂—CON(—CH₂—CH₂—CH₂— CH₂—CH₂) V-177 CH₃ H H —CH₂—CH₂—COOCH₃ V-178 CH₃ H H —CH₂—CH₂—COOC₂H₅ V-179 CH₃ H H —CH₂—CH₂—CONH₂ V-180 CH₃ H H —CH₂—CH₂—CONHCH₃ V-181 CH₃ H H —CH₂—CH₂—CON(CH₃)₂ V-182 CH₃ H H —CH₂—CH₂—CONH—CH₂—C₆H₅ V-183 CH₃ H H —CH₂—CH₂—CONH—C₆H₅ V-184 CH₃ H H —CH₂—CH₂—CONH(CH₂—C₆H₅)₂ V-185 CH₃ H H —CH₂—CH₂—CON(— CH₂—CH₂—CH₂—CH₂—) V-186 CH₃ H H —CH₂—CH₂—CON(—CH₂— (CH₂)₃—CH₂) V-187 CH₃ H H —CH₂—COCH₃ V-188 CH₃ H H —CH₂—CH₂—COCH₃ V-189 CH₃ H H —CH₂—COC₂H₅ V-190 CH₃ H H —CH₂—CH₂—COC₂H₅ V-191 CH₃ H H —CH₂—CO—C₆H₅ V-192 CH₃ H H —CH₂—CH₂—CO—C₆H₅ V-193 CH₃ H H —CH₂—CO—CH₂—C₆H₅ V-194 CH₃ H H —CH₂—CH₂—CO—CH₂—C₆H₅ V-195 CH₃ H H —CH₂—SOC₆H₅ V-196 CH₃ H H —CH₂—SOCH₃ V-197 CH₃ H H —CH₂—SO(4-CH₃—C₆H₄) V-198 CH₃ H H —CH₂—SO₂C₆H₅ V-199 CH₃ H H —CH₂—SO₂CH₃ V-200 CH₃ H H —CH₂—SO₂(4-CH₃—C₆H₄) V-201 CH₃ H H —CH₂—CH₂—SOC₆H₅ V-202 CH₃ H H —CH₂—CH₂—SOCH₃ V-203 CH₃ H H —CH₂—CH₂—SO(4-CH₃—C₆H₄) V-204 CH₃ H H —CH₂—CH₂—SO₂C₆H₅ V-205 CH₃ H H —CH₂—CH₂—SO₂CH₃ V-206 CH₃ H H —CH₂—CH₂—SO₂(4-CH₃—C₆H₄)

[0202] Table 6:

[0203] A is Me₂Val, B is Val, D is MeVal, E is Pro and F is of Formula II_(f), the substituent —(C═O)-G is in position 4 relative to the nitrogen. G is of Formula V_(g), VI_(g), VII_(g), VIII_(g) or IX_(g). No. R_(F) R¹F R²F -G VI-1 H H H —CH₃ VI-2 H H H —C₂H₅ VI-3 H H H -nC₃H₇ VI-4 H H H -isoC₃H₇ VI-5 H H H -nC₄H₉ VI-6 H H H -tertC₄H₉ VI-7 H H H -cycloC₃H₅ VI-8 H H H -cycloC₄H₇ VI-9 H H H -cycloC₅H₉ VI-10 H H H -cycloC₆H₁₁ VI-11 H H H -cycloC₇H₁₂ VI-12 H H H —CH₂—O—CH₃ VI-13 H H H —CH₂—CH₂—O—CH₃ VI-14 H H H —CH₂—C₆H₅ VI-15 H H H —C₆H₅ VI-16 H H H -(4-HO—C₆H₅) VI-17 H H H -(2-CF₃—C₆H₄) VI-18 H H H -(3-CF₃—C₆H₄) VI-19 H H H -(4-CF₃—C₆H₄) VI-20 H H H -(2-OCH₃—C₆H₄) VI-21 H H H -(3-OCH₃—C₆H₄) VI-22 H H H -(4-OCH₃—C₆H₄) VI-23 H H H -(2-SCH₃—C₆H₄) VI-24 H H H -(3-SCH₃—C₆H₄) VI-25 H H H -(4-SCH₃—C₆H₄) VI-26 H H H -(2-N(CH₃)₂—C₆H₄) VI-27 H H H -(3-N(CH₃)₂—C₆H₄) VI-28 H H H -(4-N(CH₃)₂—C₆H₄) VI-29 H H H -(4-CN—C₆H₄) VI-30 H H H -(4-Cl—C₆H₄) VI-31 H H H -(4-Br—C₆H₄] VI-32 H H H -(4-F—C₆H₄] VI-33 H H H -(4-CH₃—C₆H₄) VI-34 H H H -(2-NO₂—C₆H₄) VI-35 H H H -(3-NO₂—C₆H₄) VI-36 H H H -(4-NO₂—C₆H₄] VI-37 H H H -(2,4-OCH₃—C₆H₃) VI-38 H H H -(3,4-OCH₃—C₆H₃) VI-39 H H H -(3,4,5-OCH₃—C₆H₂) VI-40 H H H -(3,4-CH₂OCH₂—C₆H₃) VI-41 H H H -(2,3-CH₂OCH₂—C₆H₃) VI-42 H H H -2-pyridinyl VI-43 H H H -2-furanyl VI-44 H H H -2-thienyl VI-45 H H H -3-pyridinyl VI-46 H H H -3-furanyl VI-47 H H H -3-thienyl VI-48 H H H -4-pyridinyl VI-49 H H H -2-thiazolyl VI-50 H H H -2-oxazolyl VI-51 H H H -3-isoxazolyl VI-52 H H H -4-isoxazolyl VI-53 H H H -5-isoxazolyl VI-54 H H H —CF₃ VI-55 H H H —C₂F₅ VI-56 H H H —CH₃ VI-57 H H H —C₂H₅ VI-58 H H H -nC₃H₇ VI-59 H H H -tertC₄H₉ VI-60 H H H —CH₂—C₆H₅ VI-61 H H H —C₆H₅ VI-62 H H H —CH₂—COOCH₃ VI-63 H H H —CH₂—COOC₂H₅ VI-64 H H H —CF₂—COOCH₃ VI-65 H H H —CF₂—COOC₂H₅ VI-66 H H H —CH₂—CONH₂ VI-67 H H H —CH₂—CONHCH₃ VI-68 H H H —CH₂—CON(CH₃)₂ VI-69 H H H —CH₂—CONH—CH₂—C₆H₅ VI-70 H H H —CH₂—CONH—C₆H₅ VI-71 H H H —CH₂—CONH(CH₂—C₆H₅)₂ VI-72 H H H —CH₂—CON(—CH₂—CH₂— CH₂—CH₂—) VI-73 H H H —CH₂—CON(—CH₂—CH₂— CH₂—CH₂—CH₂) VI-74 H H H —CH₂—CH₂—COOCH₃ VI-75 H H H —CH₂—CH₂—COOC₂H₅ VI-76 H H H —CH₂—CH₂—CONH₂ VI-77 H H H —CH₂—CH₂—CONHCH₃ VI-78 H H H —CH₂—CH₂—CON(CH₃)₂ VI-79 H H H —CH₂—CH₂—CONH—CH₂—C₆H₅ VI-80 H H H —CH₂—CH₂—CONH—C₆H₅ VI-81 H H H —CH₂—CH₂—CONH(CH₂—C₆H₅)₂ VI-82 H H H —CH₂—CH₂—CON(—CH₂— CH₂—CH₂—CH₂—) VI-83 H H H —CH₂—CH₂—CON(—CH₂— (CH₂)₃—CH₂) VI-84 H H H —CH₂—COCH₃ VI-85 H H H —CH₂—CH₂—COCH₃ VI-86 H H H —CH₂—COC₂H₅ VI-87 H H H —CH₂—CH₂—COC₂H₅ VI-88 H H H —CH₂—CO—C₆H₅ VI-89 H H H —CH₂—CH₂—CO—C₆H₅ VI-90 H H H —CH₂—CO—CH₂—C₆H₅ VI-91 H H H —CH₂—CH₂—CO—CH₂—C₆H₅ VI-92 H H H —CH₂—SOC₆H₅ VI-93 H H H —CH₂—SOCH₃ VI-94 H H H —CH₂SO(4-CH₃—C₆H₄) VI-95 H H H —CH₂—SO₂C₆H₅ VI-96 H H H —CH₂—SO₂CH₃ VI-97 H H H —CH₂—SO₂(4-CH₃—C₆H₄) VI-98 H H H —CH₂—CH₂—SOC₆H₅ VI-99 H H H —CH₂—CH₂—SOCH₃ VI-100 H H H —CH₂—CH₂—SO(4-CH₃—C₆H₄) VI-101 H H H —CH₂—CH₂—SO₂C₆H₅ VI-102 H H H —CH₂—CH₂—SO₂CH₃ VI-103 H H H —CH₂—CH₂—SO₃(4-CH₃—C₆H₄) VI-104 CH₃ H H —CH₃ VI-105 CH₃ H H —C₂H₅ VI-106 CH₃ H H -nC₃H₇ VI-107 CH₃ H H -isoC₃H₇ VI-108 CH₃ H H -nC₄H₉ VI-109 CH₃ H H -tertC₄H₉ VI-110 CH₃ H H -cycloC₃H₅ VI-111 CH₃ H H -cycloC₄H₇ VI-112 CH₃ H H -cycloC₅H₉ VI-113 CH₃ H H -cycloC₆H₁₁ VI-114 CH₃ H H -cycloC₇H₁₂ VI-115 CH₃ H H —CH₂—O—CH₃ VI-116 CH₃ H H —CH₂—CH₃—O—CH₃ VI-117 CH₃ H H —CH₂—C₆H₅ VI-118 CH₃ H H —C₆H₅ VI-119 CH₃ H H -(4-HO-C₆H₅) VI-120 CH₃ H H -(2-CF₃—C₆H₄) VI-121 CH₃ H H -(3-CF₃—C₆H₄) VI-122 CH₃ H H -(4-CF₃—C₆H₄) VI-123 CH₃ H H -(2-OCH₃—C₆H₄) VI-124 CH₃ H H -(3-OCH₃—C₆H₄) VI-125 CH₃ H H -(4-OCH₃—C₆H₄) VI-126 CH₃ H H -(2-SCH₃—C₆H₄) VI-127 CH₃ H H -(3-SCH₃—C₆H₄) VI-128 CH₃ H H -(4-SCH₃—C₆H₄) VI-129 CH₃ H H -(2-N(CH₃)₂—C₆H₄) VI-130 CH₃ H H -(3-N(CH₃)₂—C₆H₄) VI-131 CH₃ H H -(4-N(CH₃)₂—C₆H₄) VI-132 CH₃ H H -(4-CN-C₆H₄) VI-133 CH₃ H H -(4-Cl—C₆H₄) VI-134 CH₃ H H -(4-Br—C₆H₄] VI-135 CH₃ H H -(4-F—C₆H₄] VI-136 CH₃ H H -(4-CH₃—C₆H₄) VI-137 CH₃ H H -(2-NO₂—C₆H₄) VI-138 CH₃ H H -(3-NO₂—C₆H₄) VI-139 CH₃ H H -(4-NO₂—C₆H₄] VI-140 CH₃ H H -(2,4-OCH₃—C₆H₃) VI-141 CH₃ H H -(3,4-OCH₃—C₆H₃) VI-142 CH₃ H H -(3,4,5-OCH₃—C₆H₂) VI-143 CH₃ H H -(3,4-CH₂OCH₂—C₆H₃) VI-144 CH₃ H H -(2,3-CH₂OCH₂—C₆H₃) VI-145 CH₃ H H -2-pyridinyl VI-146 CH₃ H H -2-furanyl VI-147 CH₃ H H -2-thienyl VI-148 CH₃ H H -3-pyridinyl VI-149 CH₃ H H -3-furanyl VI-150 CH₃ H H -3-thienyl VI-151 CH₃ H H -4-pyridinyl VI-152 CH₃ H H -2-thiazolyl VI-153 CH₃ H H -2-oxazolyl VI-154 CH₃ H H -3-isoxazolyl VI-155 CH₃ H H -4-isoxazolyl VI-156 CH₃ H H -5-isoxazoyl VI-157 CH₃ H H —CF₃ VI-158 CH₃ H H —C₂F₅ VI-159 CH₃ H H —CH₃ VI-160 CH₃ H H —C₂H₅ VI-161 CH₃ H H -nC₃H₇ VI-162 CH₃ H H -tertC₄H₉ VI-163 CH₃ H H —CH₂—C₆H₅ VI-164 CH₃ H H —C₆H₅ VI-165 CH₃ H H —CH₂—COOCH₃ VI-166 CH₃ H H —CH₂—COOC₂H₅ VI-167 CH₃ H H —CF₂—COOCH₃ VI-168 CH₃ H H —CF₂—COOC₂H₅ VI-169 CH₃ H H —CH₂—CONH₂ VI-170 CH₃ H H —CH₂—CONHCH₃ VI-171 CH₃ H H —CH₂—CON(CH₃)₂ VI-172 CH₃ H H —CH₂—CONH—CH₂—C₆H₅ VI-173 CH₃ H H —CH₂—CONH—C₆H₅ VI-174 CH₃ H H —CH₂—CONH(CH₂—C₆H₅)₂ VI-175 CH₃ H H —CH₂—CON(—CH₂—CH₂— CH₂—CH₂—) VI-176 CH₃ H H —CH₂—CON(—CH₂—CH₂—CH₂— CH₂—CH₂) VI-177 CH₃ H H —CH₂—CH₂—COOCH₃ VI-178 CH₃ H H —CH₂—CH₂—COOC₂H₅ VI-179 CH₃ H H —CH₂—CH₂—CONH₂ VI-180 CH₃ H H —CH₂—CH₂—CONHCH₃ VI-181 CH₃ H H —CH₂—CH₂—CON(CH₃)₂ VI-182 CH₃ H H —CH₂—CH₂—CONH—CH₂—C₆H₅ VI-183 CH₃ H H —CH₂—CH₂—CONH—C₆H₅ VI-184 CH₃ H H —CH₂—CH₂—CONH(CH₂—C₆H₅)₂ VI-185 CH₃ H H —CH₂—CH₂—CON(— CH₂—CH₂—CH₂—CH₂—) VI-186 CH₃ H H —CH₂—CH₂—CON(—CH₂— (CH₂)₃—CH₂) VI-187 CH₃ H H —CH₂—COCH₃ VI-188 CH₃ H H —CH₂—CH₂—COCH₃ VI-189 CH₃ H H —CH₂—COC₂H₅ VI-190 CH₃ H H —CH₂—CH₂—COC₂H₅ VI-191 CH₃ H H —CH₂—CO—C₆H₅ VI-192 CH₃ H H —CH₂—CH₂—CO—C₆H₅ VI-193 CH₃ H H —CH₂—CO—CH₂—C₆H₅ VI-194 CH₃ H H —CH₂—CH₂—CO—CH₂—C₆H₅ VI-195 CH₃ H H —CH₂—SOC₆H₅ VI-196 CH₃ H H —CH₂—SOCH₃ VI-197 CH₃ H H —CH₂—SO(4-CH₃—C₆H₄) VI-198 CH₃ H H —CH₂—SO₂C₆H₅ VI-199 CH₃ H H —CH₂—SO₂CH₃ VI-200 CH₃ H H —CH₂—SO₂(4-CH₃—C₆H₄) VI-201 CH₃ H H —CH₂—CH₂—SOC₆H₅ VI-202 CH₃ H H —CH₂—CH₂—SOCH₃ VI-203 CH₃ H H —CH₂—CH₂—SO(4-CH₃—C₆H₄) VI-204 CH₃ H H —CH₂—CH₂—SO₂C₆H₅ VI-205 CH₃ H H —CH₂—CH₂—SO₂CH₃ VI-206 CH₃ H H —CH₂—CH₂—SO₂(4-CH₃—C₆H₄)

[0204] Table 7:

[0205] A is Me₂Val, B is Val, D is MeVal, E is Pro and F is of Formula III_(f), the substituent —(C═O)-G is in position 2 relative to the nitrogen and a_(f) is 1. G is of Formula II_(g) or III_(g). The compounds are mixtures of diasteromers, configuration in F is R, S (cis) or S,R (cis). No. R_(f) -G VII-1 H —NH—CH₃ VII-2 H —NH—CH₂—C₆H₅ VII-3 H —NH-isoC₃H₇ VII-4 H —NH—C₆H₅ VII-5 H 1,3-Thiazol-2-yl-amide VII-6 H —NH—CH₃ VII-7 H —NH—CH₃ VII-8 H —NH—C₂H₅ VII-9 H —NH-nC₃H₇ VII-10 H —NH-nC₄H₉ VII-11 H —NH-tertC₄H₉ VII-12 H —NH-cycloC₃H₅ VII-13 H —NH-cycloC₄H₇ VII-14 H —NH-cycloC₅H₉ VII-15 H —NH-cycloC₆H₁₁ VII-16 H —NH-cycloC₇H₁₂ VII-17 H —NH—CH₂—O—CH₃ VII-18 H —NH—CH₂—CH₂—O—CH₃ VII-19 H —NH-1-adamantyl VII-20 H —NH-(4-HO—C₆H₅) VII-21 H —NH-(2-CF₃—C₆H₄) VII-22 H —NH-(3-CF₃—C₄H₄) VII-23 H —NH-(4-CF₃—C₆H₄) VII-24 H —NH-(2-OCH₃—C₆H₄) VII-25 H —NH-(3-OCH₃—C₆H₄) VII-26 H —NH-(4-OCH₃—C₆H₄) VII-27 H —NH-(2-SCH₃—C₆H₄) VII-28 H —NH-(3-SCH₃—C₆H₄) VII-29 H —NH-(4-SCH₃—C₆H₄) VII-30 H —NH-(2-N(CH₃)₂—C₆H₄) VII-31 H —NH-(3-N(CH₃)₂—C₆H₄) VII-32 H —NH-(4-N(CH₃)₂—C₆H₄) VII-33 H —NH-(4-CN—C₆H₄) VII-34 H —NH-(4-Cl—C₆H₄) VII-35 H —NH-(4-Br—C₆H₄] VII-36 H —NH-(4-F—C₆H₄] VII-37 H —NH-(4-CH₃—C₆H₄) VII-38 H —NH-(2-NO₂—C₆H₄) VII-39 H —NH-(3-NO₂—C₆H₄) VII-40 H —NH-(4-NO₂—C₆H₄] VII-41 H —NH-(2,4-OCH₃—C₆H₃) VII-42 H —NH-(3,4-OCH₃—C₆H₃) VII-43 H —NH-(3,4,5-OCH₃—C₆H₂) VII-44 H —NH-(3,4-CH₂OCH₂—C₆H₃) VII-45 H —NH-(2,3-CH₂OCH₂—C₆H₃) VII-46 H —NH-2-pyridinyl VII-47 H —NH-2-furanyl VII-48 H —NH-2-thienyl VII-49 H —NH-3-pyridinyl VII-50 H —NH-3-furanyl VII-51 H —NH-3-thienyl VII-52 H —NH-4-pyridinyl VII-53 H —NH-2-oxazolyl VII-54 H —NH-3-isoxazolyl VII-55 H —NH-4-isoxazolyl VII-56 H —NH-5-isoxazoyl VII-57 H —NH-2R-(but-2-yl) VII-58 H —NH-2S-(but-2-yl) VII-59 H —NH—O—CH₃ VII-60 H —N(CH₃)(OCH₃) VII-61 H —N(—(CH₂)₃—O—) VII-62 H —NH—O—CH₂—C₆H₅ VII-63 H —N(CH₃)(O—CH₂—C₆H₅) VII-64 H —N(—(CH₂)₂—CH(C₆H₅)—O—) VII-65 H —NH—O—C₂H₅ VII-66 H —N(C₂H₅)(OC₂H₅) VII-67 H —N(CH₃)(OC₂H₅) VII-68 H —NH—O-isoC₃H₇ VII-69 H —N(CH₃)(O-isoC₃H₇) VII-70 H —NH—O-nC₃H₇ VII-71 H —N(CH₃)(O-nC₃H₇) VII-72 H —NH—O-nC₄H₉ VII-73 H —N(CH₃)(O-nC₄H₉) VII-74 H —NH—O-tertC₄H₉ VII-75 H —N(CH₃)(O-tertC₄H₉) VII-76 H —NH—O—C₆H₅ VII-77 H —N(CH₃)(O—C₆H₅) VII-78 H —N(CH₃)₂ VII-79 H —N(CH₂—C₆H₅)₂ VII-80 H —N(C₂H₅)₂ VII-81 H —N(isoC₃H₇)₂ VII-82 H —N(nC₃H₇)₂ VII-83 H —N(nC₄H₉)₂ VII-84 H —N(C₆H₅)₂ VII-85 H —NH—CH₂—CH₂—OH VII-86 H —NH—(CH₂)₃—OH VII-87 H —NH(—(CH₂)₂—CH(C₆H₅)—OH) VII-88 H —NH—(CH₂)₄—OH VII-89 H —NH(—CH(CH₃)—CH₂—OH) VII-90 H —NH(—CH₂—CH(CH₃)—OH) VII-91 H —NH(—CH(CH₃)—(CH₂)₂—OH) VII-92 H —NH(—(CH₂)₂—CH(CH₃)—OH) VII-93 CH₃ —NH—CH₃ VII-94 CH₃ —NH—CH₂—C₆H₅ VII-95 CH₃ —NH-isoC₃H₇ VII-96 CH₃ —NH—C₆H₅ VII-97 CH₃ —NH—C₂H₅ VII-98 CH₃ —NH-nC₃H₇ VII-99 CH₃ —NH-nC₄H₉ VII-100 CH₃ —NH-tertC₄H₉ VII-101 CH₃ —NH-cycloC₃H₅ VII-102 CH₃ —NH-cycloC₄H₇ VII-103 CH₃ —NH-cycloC₅H₉ VII-104 CH₃ —NH-cycloC₆H₁₁ VII-105 CH₃ —NH-1-adamantyl VII-106 CH₃ —NH-2R-(but-2-yl) VII-107 CH₃ —NH-2S-(but-2-yl) VII-108 CH₃ —NH—O—CH₃ VII-109 CH₃ —N(CH₃)(OCH₃) VII-110 CH₃ —N(—(CH₂)₃—O—) VII-111 CH₃ —N(CH₃)₂ VII-112 CH₃ —N(CH₂—C₆H₅)₂ VII-113 CH₃ —N(C₂H₅)₂ VII-114 CH₃ —N(isoC₃H₇)₂ VII-115 CH₃ —N(nC₃H₇)₂ VII-116 CH₃ —N(nC₄H₉)₂ VII-117 CH₃ —N(C₆H₅)₂

[0206] Table 8:

[0207] A is Me₂Val, B is Val, D is MeVal, E is Pro and F is of Formula III_(f), the substituent —(C═O)-G is in position 2 relative to the nitrogen and a_(f) is 1. G is of Formula II_(g) or III_(g).

[0208] The compounds are mixtures of diasteromers, configuration in F is either R, R (trans) or S,S (trans). No. R_(f) -G VIII-1 H —NH—CH₃ VIII-2 H —NH—CH₂—C₆H₅ VIII-3 H —NH-isoC₃H₇ VIII-4 H —NH—C₆H₅ VIII-5 H 1,3-Thiazol-2-yl-amide VIII-6 H —NH—CH₃ VIII-7 H —NH—CH₃ VIII-8 H —NH—C₂H₅ VIII-9 H —NH-nC₃H₇ VIII-10 H —NH-nC₄H₉ VIII-11 H —NH-tertC₄H₉ VIII-12 H —NH-cycloC₃H₅ VIII-13 H —NH-cycloC₄H₇ VIII-14 H —NH-cycloC₅H₉ VIII-15 H —NH-cycloC₆H₁₁ VIII-16 H —NH-cycloC₇H₁₂ VIII-17 H —NH—CH₂-O-CH₃ VIII-18 H —NH—CH₂—CH₂—O-CH₃ VIII-19 H —NH-1-adamantyl VIII-20 H —NH-(4-HO-C₆H₅) VIII-21 H —NH-(2-CF₃—C₆H₄) VIII-22 H —NH-(3-CF₃—C₆H₄) VIII-23 H —NH-(4-CF₃—C₆H₄) VIII-24 H —NH-(2-OCH₃—C₆H₄) VIII-25 H —NH-(3-OCH₃—C₆H₄) VIII-26 H —NH-(4-OCH₃—C₆H₄) VIII-27 H —NH-(2-SCH₃—C₆H₄) VIII-28 H —NH-(3-SCH₃—C₆H₄) VIII-29 H —NH-(4-SCH₃—C₆H₄) VIII-30 H —NH-(2-N(CH₃)₂—C₆H₄) VIII-31 H —NH-(3-N(CH₃)₂-C₆H₄) VIII-32 H —NH-(4-N(CH₃)₂-C₆H₄) VIII-33 H —NH-(4-CN-C₆H₄) VIII-34 H —NH-(4-Cl-C₆H₄) VIII-35 H —NH-(4-Br-C₆H₄] VIII-36 H —NH-(4-F-C-₆H₄] VIII-37 H —NH-(4-CH₃-C₆H₄) VIII-38 H —NH-(2-NO₂-C₄H₄) VIII-39 H —NH-(3-NO₂-C₆H₄) VIII-40 H —NH-(4-NO₂-C₆H₄] VIII-41 H —NH-(2,4-OCH₃-C₆H₃) VIII-42 H —NH-(3,4-OCH₃-C₆H₃) VIII-43 H —NH-(3,4,5-OCH₃-C₆H₂) VIII-44 H —NH-(3,4-CH₂OCH₂-C₆H₃) VIII-45 H —NH-(2,3-CH₂OCH₂-C₆H₃) VIII-46 H —NH-2-pyridinyl VIII-47 H —NH-2-furanyl VIII-48 H —NH-2-thienyl VIII-49 H —NH-3-pyridinyl VIII-50 H —NH-3-furanyl VIII-51 H —NH-3-thienyl VIII-52 H —NH-4-pyridinyl VIII-53 H —NH-2-oxazolyl VIII-54 H —NH-3-isoxazolyl VIII-55 H —NH-4-isoxazolyl VIII-56 H —NH-5-isoxazoyl VIII-57 H —NH-2R-(but-2-yl) VIII-58 H —NH-2S-(but-2-yl) VIII-59 H —NH—O—CH₃ VIII-60 H —N(CH₃) (OCH₃) VIII-61 H —N(—(CH₂)₃—O—) VIII-62 H —NH—O—CH₂—C₆H₅ VIII-63 H —N(CH₃) (O—CH₂—C₆H₅) VIII-64 H —N(—(CH₂)₂—CH(C₆H₅)—O—) VIII-65 H —NH—O—C₂H₅ VIII-66 H —N(C₂H₅) (OC₂H₅) VIII-67 H —N(CH₃) (OC₂H₅) VIII-68 H NH—O-isoC₃H₇ VIII-69 H —N(CH₃) (O-isoC₃H₇) VIII-70 H —NH—O-nC₃H₇ VIII-71 H —N(CH₃) (O-nC₃H₇) VIII-72 H —NH—O-nC₄H₉ VIII-73 H —N(CH₃) (O-nC₄H₉) VIII-74 H —NH—O-tertC₄H₉ VIII-75 H —N(CH₃) (O-tertC₄H₉) VIII-76 H —NH—O—C₆H₅ VIII-77 H —N(CH₃) (O—C₆H₅) VIII-78 H —N(CH₃)₂ VIII-79 H —N(CH₂—C₆H₅)₂ VIII-80 H —N(C₂H₅)₂ VIII-81 H —N(isoC₃H₇)₂ VIII-82 H —N(nC₃H₇)₂ VIII-83 H —N(nC₄H₉)₂ VIII-84 H —N(C₆H₅)₂ VIII-85 H —NH—CH₂—CH₂—OH VIII-86 H —NH—(CH₂)₃—OH VIII-87 H —NH(—(CH₂)₂—CH(C₆H₅) —OH) VIII-88 H —NH—(CH₂)₄—OH VIII-89 H —NH(—CH(CH₃)—CH₂—OH) VIII-90 H —NH(—CH₂CH(CH₃) —OH) VIII-91 H —NH(—CH(CH₃)—(CH₂)₂OH) VIII-92 H —NH(—(CH₂)₂—CH(CH₃)—OH) VIII-93 CH₃ —NH—CH₃ VIII-94 CH₃ —NH—CH₂—C₆H₅ VIII-95 CH₃ —NH-isoC₃H₇ VIII-96 CH₃ —NH—C₆H₅ VIII-97 CH₃ —NH—C₂H₅ VIII-98 CH₃ —NH-nC₃H₇ VIII-99 CH₃ —NH-nC₄H₉ VIII-100 CH₃ —NH-tertC₄H₉ VIII-101 CH₃ —NH-cycloC₃H₅ VIII-102 CH₃ —NH-cycloC₄H₇ VIII-103 CH₃ —NH-cycloC₅H₉ VIII-104 CH₃ —NH-cycloC₆H₁₁ VIII-105 CH₃ —NH-1-adamantyl VIII-106 CH₃ —NH-2R-(but-2-yl) VIII-107 CH₃ —NH-2S-(but-2-yl) VIII-108 CH₃ —NH—O—CH₃ VIII-109 CH₃ —N(CH₃) (OCH₃) VIII-110 CH₃ —N(—(CH₂)₃—O—) VIII-111 CH₃ —N(CH₃)₂ VIII-112 CH₃ —N(CH₂—C₆H₅)₂ VIII-113 CH₃ —N(C₂H₅)₂ VIII-114 CH₃ —N(isoC₃H₇)₂ VIII-115 CH₃ —N(nC₃H₇)₂ VIII-116 CH₃ —N(nC₄H₉)₂ VIII-117 CH₃ —N(C₆H₅)₂

[0209] Mass spectrometry data of selected examples: I-1 2-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄C(O)NHCH₃ FAB-MS: 588 (M + H⁺) I-2 2-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄C(O)NHCH₂C₆H₅ FAB-MS: 664 (M + H⁺) I-3 2-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄C(O)NHCH(CH₃)₂ FAB-MS: 616 (M + H⁺) I-4 2-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄C(O)NHC₆H₅ FAB-MS: 650 (M + H⁺) I-5 2-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄C(O)NH(thiazol-2-yl) FAB-MS: 657 (M + H⁺) I-6 2(Me₂Val-Val-MeVal-ProNH)-4, 5-bis(methoxy)C₆H₂C(O)NHCH₃ FAB-MS: 649 (M + H⁺) I-7 2-(Me₂ValVal-MeVal-ProNH)-3-cyclopentanyl-C₆H₃C(O)NHCH₃ FAB-MS: 656 (M + H⁺) I-64 2-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄—CO—N(—(CH₂)₂— CH(C₆H₅)O—) (mix. of diastereomers) FAB-MS: 706 (M + H⁺) I-79 2-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄—CO—N(CH₂C₆H₅)₂ FAB-MS: 754 (M +H⁺) I-86 2-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄—CO—NH—(—(CH₂)₃ — OH) FAB-MS: 632 (M + H⁺) I-87 2-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄C(O)NH((CH₂)₂CH(C₆H₅) OH) FAB-MS: 708 (M + H⁺) I-143 2-(Me₂Val-Val-MeVal-Pro-N(CH₃))—C₆H₄—CONHCH₃ FAB-MS: 601 (M + H⁺) II-1 3-(Ne₂Val-Val-MeVal-Pro-NH)—C₆H₄—CO—NHCH₃ FAB-MS: 588 (M + H⁺) II-2 3-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄—CO—NH CH₂C₆H₅ FAB-MS: 664 (M + H⁺) IV-1 2-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄—CO—CH₃ FAB-MS: 609 (M + H⁺) IV-15 2-(Me₂Val-Val-MeVal-Pro-NH)—C₆H₄—CO—C₆H₅ FAB-MS: 635 (M + H+)

Evaluation of Biological Activity

[0210] In Vitro Methodology

[0211] Cytotoxicity was measured using a standard methodology for adherent cell lines, such as the microculture tetrazolium assay (MTT). Details of this assay have been published (Alley, M. C. et al., Cancer Research 48: 589-601, 1988). Exponentially growing cultures of tumor cells such as the HT-29 colon carcinoma or LX-1 lung tumor were used to make microtiter plate cultures. Cells were seeded at 5000-20,000 cells per well in 96-well plates (in 150 mL of media), and grown overnight at 37° C. Test compounds were added, in 10-fold dilutions varying from 10⁻⁴ M to 10⁻¹⁰ M. Cells were then incubated for 48 hours. To determine the number of viable cells in each well, the MTT dye was added (50 mL of a 3 mg/mL solution of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide in saline). This mixture was incubated at 37° C. for 5 hours, and then 50 mL of 25% SDS, pH 2, was added to each well. After an overnight incubation, the absorbance of each well at 550 nm was read using an ELISA reader. The values for the mean+/−SD of data from replicated wells were calculated, using the formula % T/C (% viable cells treated/control). The concentration of test compound which gives a T/C of 50% growth inhibition was designated as the IC₅₀. Compound No. IC₅₀ (mol/l) I-1   4 × 10⁻⁷ I-2 >10⁻⁶ I-3   5 × 10⁻⁷ I-4   4 × 10⁻⁷ I-5 1.5 × 10⁻⁷ I-6   2 × 10⁻⁷ I-7   4 × 10⁻⁷ I-60   4 × 10⁻⁷ I-64 2.5 × 10⁻⁷ I-86   6 × 10⁻⁷ I-87   2 × 10⁻⁷ II-1 >10⁻⁶ II-2 >10⁻⁶ IV-1 >10⁻⁶ IV-15   7 × 10⁻⁸ VII-2 >10⁻⁶

[0212] In Vivo Methodology

[0213] Compounds of this invention may be further tested in any of the various preclinical assays for in vivo activity which are indicative of clinical utility. Such assays are conducted with nude mice into which tumor tissue, preferably of human origin, has been transplanted (“xenografted”), as is well known in this field. Test compounds are evaluated for their anti-tumor efficacy following administration to the xenograft-bearing mice.

[0214] More specifically, human tumors which have been grown in athymic nude mice are transplanted into new recipient animals, using tumor fragments which are about 50 mg in size. The day of transplantation is designated as day 0. Six to ten days later, the mice are treated with the test compounds given as an intravenous or intraperitoneal injection, in groups of 5-10 mice at each dose. Compounds are given daily for 5 days, 10 days or 15 days, at doses from 10-100 mg/kg body weight. Tumor diameters and body weights are measured twice weekly. Tumor masses are calculated using the diameters measured with Vernier calipers, and the formula:

(length×width²)/2=mg of tumor weight

[0215] Mean tumor weights are calculated for each treatment group, and T/C values determined for each group relative to the untreated control tumors.

[0216] The novel compounds of the present invention show good in vitro activity in the above-mentioned assay system.

Equivalents

[0217] While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described specifically herein. Such equivalents are intended to be encompassed in the scope of the claims. 

We claim:
 1. A compound of the formula A-B-D-E-F-G, or a salt thereof with a pharmaceutically acceptable acid, wherein A is a proline derivative of Formula II_(a),

wherein n_(a) is 0 to 3; R_(a) is hydrogen, or unsubstituted or fluorine-substituted normal, branched or cyclic C₁-C₃-alkyl; R¹ _(a) is hydrogen, C₁-C ₃-alkyl, phenyl, or substituted phenyl; or R_(a) and R¹ _(a) together form a propylene bridge; and R² _(a), R³ _(a), R⁴ _(a) and R⁵ _(a) are each, independently, hydrogen or alkyl; or an α-amino acid derivative of Formula III_(a),

wherein R_(a) is hydrogen or unsubstituted or fluorine-substituted C₁-C₃-alkyl; R¹ _(a) is hydrogen or C₁-C₄-alkyl; R⁶ _(a) is alkyl, substituted alkyl, alkenyl, phenyl or substituted phenyl; or R¹ _(a) is an alkyl group and R⁶ _(a) is C₁-C₆-alkyl, cycloalkylmethyl, benzyl or substituted benzyl; and R⁷ _(a) is hydrogen or alkyl; or an α-amino acid derivative of Formula IV_(a),

wherein m_(a) is 1 or 2; R⁷ _(a) is hydrogen or alkyl; R_(a) is hydrogen, or unsubstituted or fluorine-substituted alkyl; or an α-amino acid derivative of Formula V_(a),

wherein R⁷ _(a) is hydrogen or alkyl and R_(a) is hydrogen, or unsubstituted or fluorine-substituted alkyl; or an α-amino acid of Formula VI_(a),

wherein R_(a) is hydrogen, or unsubstituted or fluorine-substituted alkyl; R¹ _(a) is hydrogen, alkyl, phenyl, or substituted phenyl; or R_(a) and R¹ _(a) together form a propylene bridge; and X_(a) is hydroxy, alkoxy or fluorine; or an α-amino acid of Formula VII_(a),

wherein R_(a) is hydrogen, or unsubstituted or fluorine-substituted alkyl; R¹ _(a) is hydrogen, alkyl, phenyl, or substituted phenyl; or R_(a) and R¹ _(a) together form a propylene bridge; and R² _(a), R³ _(a), R⁴ _(a) and R⁵ _(a) are each, independently, hydrogen or alkyl; or an α-amino acid residue of Formula VIII_(a),

wherein R_(a) is hydrogen, or unsubstituted or fluorine-substituted alkyl; or a 2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivative of Formula IX_(a),

wherein the 3-carbonyl moiety is in the endo or exo position, Z_(a) is a single bond or a double bond, and R_(a) is hydrogen or unsubstituted or fluorine-substituted alkyl; or an α-amino acid residue of Formula X_(a),

wherein n_(a) is 1, 2 or 3, and R⁷ _(a) is hydrogen or alkyl and R_(a) is hydrogen , unsubstituted alkyl or fluorine-substituted alkyl; B is a valyl, isoleucyl, allo-isoleucyl, norvalyl, 2-tert-butylglycyl or 2-ethylglycyl residue; or an α-amino acid residue of Formula II_(b),

wherein R¹ _(b) is hydrogen, and R² _(b) is alkyl or alkenyl; or R¹ _(b) and R² _(b) together form an isopropylidene group; D is an N-alkylvalyl, N-alkyl-2-ethylglycyl, N-alkyl-2-tert-butylglycyl, N-alkylnorleucyl, N-alkylisoleucyl, N-alkyl-allo-isoleucyl or N-alkylnorvalyl residue; or an α-amino acid residue of Formula II_(d),

wherein R_(d) is hydrogen, or unsubstituted or fluorine-substituted alkyl; R¹ _(d) is hydrogen; and R² _(d) is alkyl, substituted alkyl or alkenyl; or R¹ _(d) and R² _(d) together form an isopropylidene group; or an α-amino acid residue of Formula III_(d),

wherein n_(d) is 1 or 2; R³ _(d) is hydrogen, alkyl or fluorine-substituted alkyl; and X_(d) is hydrogen; or n_(d) is 1 and X_(d) is fluorine, hydroxy, methoxy, or ethoxy; E is a prolyl, thiazolidinyl-4-carbonyl, homoprolyl,or hydroxyprolyl residue; or an α-amino acid residue of Formula II_(e),

wherein n_(e) is 0, 1 or 2, R¹ _(e) is hydrogen, or unsubstituted or fluorine-substituted alkyl; R² _(e) and R³ _(e) are each, independently, hydrogen or alkyl; R⁴ _(e) is hydrogen, hydroxy or alkoxy; and R⁵ _(e) is hydrogen or fluorine; or n_(e) is 1 and R³ _(e) and R⁴ _(e) together form a double bond; or n_(e) is 1 and R⁴ _(e) and R⁵ _(e) together form a double-bonded oxygen diradical; or n_(e) is 1 or 2 and R¹ _(e) and R² _(e) together form a double bond; or an aminocyclopentanecarboxylic acid residue of Formula III_(e),

wherein R_(e) is alkyl and R¹ _(e) is hydrogen, or unsubstituted or fluorine-substituted alkyl; F is an aminobenzoyl derivative of Formula II_(f),

wherein R_(f) is a hydrogen atom or an alkyl group; the carbonyl group is ortho, meta, or para to the nitrogen atom; R¹ _(f) and R² _(f) are each, independently, a hydrogen atom; a halogen atom; a C₁-C₄-alkyl group; a methoxy, ethoxy, trifluoromethyl, nitro, cyano, amino or dimethyalmino group; or R¹ _(f) and R² _(f) can together form a dioxymethylene group; or F is an aminocycloalkanecarboxylic acid residue of Formula III_(f),

wherein R_(f) is a hydrogen atom or an alkyl group; a_(f) is 0, 1 or 2; and the carbonyl group is in position 2 or position 3 of the cycloalkane ring relative to the nitrogen atom; and G is a substituted or unsubstituted amino, hydrazido, aminoxy, oximato, arylalkyl, heteroarylalkyl, aryl, heteroaryl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonylalkyl, aminocarbonyl, alkylcarbonylalkyl, alkylcarbonyl, arylcarbonylalkyl, arylcarbonyl, alkylsulfinylalkyl, alkylsulfinyl, arylsulfinylalkyl, arylsulfinyl, alkylsulfonylalkyl, alkylsulfonyl, arylsulfonylalkyl or arylsulfonyl group.
 2. The compound of claim 1 wherein the pharmaceutically acceptable acid is hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid or acetylglycine.
 3. The compound of claim 1 wherein G is a monovalent radical of Formula II_(g),

wherein R¹ _(l) is a hydrogen atom, a normal or branched, saturated or unsaturated C₁-C₁₈-alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted aryl-C₁-C₆-alkoxy group, a substituted or unsubstituted aryloxy-C₁-C₆-alkoxy group, wherein the aryl substituents comprise one or more halogen atoms or one or more C₁-C₄-alkyl, methoxy, ethoxy, trifluoromethyl, nitro or dioxymethylene groups; or a heteroaryl-C₁-C₆-alkoxy group, wherein the heteroaryl group is derived from imidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine; and R² _(l) is a hydrogen atom, a normal or branched C₁-C₁₈-alkyl group, a normal C₁-C₁₈ alkenyl group, a C₃-C₁₀-cycloalkyl group, an aryl group, or a substituted aryl group, wherein the aryl substituents comprise one or more halogen atoms, or one or more alkyl, alkoxy, dioxymethylene, trifluoromethyl or nitro groups; or a heteroaryl or substituted heteroaryl group derived from imidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine and the heteroaryl substituents comprise one or more C₁-C₆-alkyl, hydroxyl or phenyl groups; or a monovalent radical of Formula II_(l),

wherein a_(l) is 0, 1, 2, 3, 4, or 5; R³ _(l) is a methyl, ethyl, normal propyl or isopropyl group; R⁴ _(l) is a saturated or partially unsaturated carbocyclic system which contains from 3 to 10 carbon atoms, an aryl group, or a substituted aryl group, wherein the aryl substituents comprise one or more halogen atoms or one or more alkoxy, dioxymethylene, trifluoromethyl, nitro, cyanof C₁-C₇-alkoxycarbonyl, C₁-C₇-alkylsulfonyl, amino, or C₁-C₇-dialkylamino groups; or a substituted or unsubstituted heteroaryl group derived from imidazole, pyrrole, thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4- or 1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole, pyrazine, pyridazine, pyrimidine, pyridine, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzopyran, indole, isoindole, indazole or quinoline, and the heteroaryl group substituents comprise one or more C₁-C₆-alkyl, hydroxyl or phenyl groups; or a monovalent radical of Formula III_(l), —(CH₂)₂-W_(l)-R⁵ _(l)  (III_(l)), wherein W_(l) is an NR⁶ _(l) group, an oxygen atom or a sulfur atom, R⁵ _(l) and R⁶ _(l) are each, independently, a hydrogen atom or a C₁-C₄-alkyl, C₃-C₇-cycloalkyl, aryl, arylmethyl or substituted aryl or arylmethyl group, wherein the aryl substituents comprise one or more halogen atoms or one or more alkoxy, dioxymethylene, trifluoromethyl, nitro, cyano, C₁-C₇-alkoxycarbonyl, C₁-C₇-alkylsulfonyl, amino, or C₁-C₇-dialkylamino groups; or R⁶ _(l) is a C₁-C₁₈-alkanoyl or benzoyl group; or a monovalent radical of Formula IV_(l), —(CH₂)_(b) _(l) -Z_(l)  (IV_(l)), b_(l) is 2, 3, or 4 and Z_(l) is a formyl, aminocarbonyl, hydrazinocarbonyl, cyclic acetal, cyclic thioacetal, acyclic acetal or acyclic thioacetal group; or a monovalent radical of Formula V_(l),

b_(l) is 2, 3, or 4; R⁷ _(l) is a polyglycol group of the formula —O—(CH₂—CH₂—O)_(dl)—CH₃; and d_(l) is between about 2 and about 4, or between about 40 and about 90; or a monovalent radical of Formula VI_(l),

wherein R⁸ _(l) is a hydrogen atom, or a C₁-C₄ alkanoyl, C₁-C₄ alkyl, benzoyl, or benzyl group.
 4. The compound of claim 1 wherein G is a β-hydroxy amino group of Formula III_(g),

R⁹ _(l) is a hydrogen atom, or a C₁-C₆-alkyl, aryl or substituted aryl group wherein the aryl substituents comprise one or more halogen atoms or one or more alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano, C₁-C₇-alkoxycarbonyl, C₁-C₇-alkylsulfonyl, amino, or C₁-C₇-dialkylamino groups; and R¹⁰ _(l) is a hydrogen atom, a methyl group or a phenyl group.
 5. The compound of claim 1 wherein G is a hydrazido group of Formula IV_(g),

wherein R¹¹ _(l) is a hydrogen atom and R¹² _(l) is a hydrogen atom, a normal or branched C₁-C₈-alkyl group, a C₃-C₈-cycloalkyl group, a C₃-C₈-cycloalkyl-C₁-C₄-alkyl group, an aryl-C₁-C₄-alkyl group, an aryl group, a substituted aryl group, wherein the aryl substituents comprise one or more halogen atoms or one or more alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano, C₁-C₇-alkoxycarbonyl, C₁-C₇-alkylsulfonyl, amino, or C₁-C₇-dialkylamino groups; or a heteroaryl group, a heteroaryl-C₁-C₄-alkyl group or a substituted heteroaryl group derived from imidazole, pyrrole, thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4- or 1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole, pyrazine, pyridazine, pyrimidine, pyridine, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzopyran, indole, isoindole, indazole or quinoline and the heteroaryl substituents comprise one or more C₁-C₆-alkyl, hydroxyl or phenyl groups.
 6. The compound of claim 1 wherein G is a monovalent radical of the formula —O—R¹³ _(l) or of the formula —S—R¹³ _(l), and R¹³ _(l) is a C₃-C₁₀-cycloalkyl, straight-chain or branched C₂-C₁₆-alkenylmethyl, C₁-C₁₆-alkyl or halogen-substituted C₁-C₁₆-alkyl group; R¹³ _(l) is a monovalent radical of the formula —(CH₂)_(el)—R¹⁴ _(l), e_(l) is 1, 2, or 3, and R¹⁴ _(l) is a saturated or partially unsaturated C₃-C₁₀ carbocyclic group; R¹³ _(l) is a monovalent radical of the formula —[CH₂—CH═C(CH₃)— CH₂]_(fl)—H, and f_(l) is 1, 2, 3, or 4; R¹³ _(l) is a monovalent radical of the formula —[CH₂—CH₂—O]_(gl)—CH₃, and g_(l) is between about 2 and about 4, or between about 40 and about 90; R¹³ _(l) is a monovalent radical of the formula —(CH₂)_(hl)—X, h_(l) is 0, 1, 2, or 3; and X is an aryl or substituted aryl group wherein the aryl substituents comprise one or more halogen atoms or one or more alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano, C₁-C₇-alkoxycarbonyl, C₁-C₇-alkylsulfonyl, amino, or C₁-C₇-dialkylamino groups; or a heteroaryl or substituted heteroaryl group derived from imidazole, pyrrole, thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4- or 1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole, pyrazine, pyridazine, pyrimidine, pyridine, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzopyran, indole, isoindole, indazole or quinoline and the heteroaryl substituents comprise one or more C₁-C₆-alkyl, hydroxyl or phenyl groups; R¹³ _(l) is a monovalent radical of the formula —(CH₂)_(bl)-W_(l)-R⁵ _(l), b_(l) is 2, 3, or 4, W_(l) is an oxygen atom, a sulfur atom or an NR⁶ _(l) group; R⁵ _(l) is a saturated carbocyclic system which contains from about 3 to about 10 carbon atoms, a partially unsaturated carbocyclic system containing from about 3 to about 10 carbon atoms, an aryl or substituted aryl group wherein the aryl substituents comprise one or more halogen atoms or one or more alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano, C₁-C₇-alkoxycarbonyl, C₁-C₇-alkylsulfonyl, amino, or C₁-C₇-dialkylamino groups; a heteroaryl or substituted heteroaryl group derived from imidazole, pyrrole, thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4- or 1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole, pyrazine, pyridazine, pyrimidine, pyridine, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzopyran, indole, isoindole, indazole or quinoline and the heteroaryl substituents comprise one or more C₁-C₆-alkyl, hydroxyl or phenyl groups; and R⁶ _(l) is a hydrogen atom, or a C₁-C₄ alkyl, C₃-C₇ cycloalkyl, C₁-C₁₈-alkanoyl, benzoyl, arylmethyl, aryl or substituted aryl or arylmethyl group, wherein the aryl substituents comprise one or more halogen atoms or one or more alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano, C₁-C₇-alkoxycarbonyl, C₁-C₇-alkylsulfonyl, amino, or C₁-C₇-dialkylamino groups.
 7. The compound of claim 1 wherein G is an aminoxy group of the formula —O—N(R¹⁶ _(l))(R¹⁵ _(l)), wherein R¹⁵ _(l) and R¹⁶ _(l) are each, independently, a hydrogen atom, a normal or branched C₁-C₈ alkyl group, a halogen-substituted normal or branched C₁-C₈-alkyl group, a C₃-C₈-cycloalkyl group, a C₃-C₈-cycloalkyl-C₁-C₄ alkyl group, an aryl-C₁-C₄-alkyl group, an aryl group or a substituted aryl-C₁-C₄-alkyl or aryl group, wherein the aryl substituents comprise one or more halogen atoms or one or more alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano, C₁-C₇-alkoxycarbonyl, C₁-C₇-alkylsulfonyl, amino, or C₁-C₇-dialkylamino groups; a heteroaryl or substituted heteroaryl group derived from imidazole, pyrrole, thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4- or 1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole, pyrazine, pyridazine, pyrimidine, pyridine, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzopyran, indole, isoindole, indazole or quinoline and the heteroaryl substituents comprise one or more C₁-C₆-alkyl, hydroxyl or phenyl groups; or R¹⁵ _(l) and R¹⁶ _(l) together with the nitrogen atom form a heterocyclic ring structure comprising 5, 6, or 7 atoms.
 8. The compound of claim 1 wherein G is a oximato group of the formula —O—N═C(R¹⁵ _(l))(R¹⁶ _(l)), wherein R¹⁵ _(l) and R¹⁶ _(l) are each, independently, a hydrogen atom, a normal or branched C₁-C₈ alkyl group, a halogen-substituted normal or branched C₁-C₈-alkyl group, a C₃-C₈-cycloalkyl group, a C₃-C₈-cycloalkyl-C₁-C₄ alkyl group, an aryl-C₁-C₄-alkyl group, an aryl group or a substituted aryl-C₁-C₄-alkyl or aryl group, wherein the aryl substituents comprise one or more halogen atoms or one or more alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano, C₁-C₇-alkoxycarbonyl, C₁-C₇-alkylsulfonyl, amino, or C₁-C₇-dialkylamino groups; a heteroaryl or substituted heteroaryl group derived from imidazole, pyrrole, thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4- or 1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole, pyrazine, pyridazine, pyrimidine, pyridine, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzopyran, indole, isoindole, indazole or quinoline and the heteroaryl substituents comprise one or more C₁-C₆-alkyl, hydroxyl or phenyl groups; or R¹⁵ _(l) and R¹⁶ _(l), together with the carbon atom, form a cyclic system, a cyclic system fused to an aromatic ring system or a cyclic system selected from the group consisting of:


9. The compound of claim 1 wherein G is a hydrogen atom, a normal or branched C₁-C₈-alkyl group, a halogen-substituted normal or branched C₁-C₈-alkyl group, a C₃-C₈ cycloalkyl group, or a C₃-C₈-cycloalkyl-C₁-C₄-alkyl group.
 10. The compound of claim 1 wherein G is a monovalent radical of Formula V_(g), —(CH₂)_(a) _(g) —R¹⁷ _(l)  (V_(g)) a_(g) is 0, 1, or 2, and R¹⁷ _(l) is an aryl group or a substituted aryl group wherein the aryl substituents comprise one or more halogen atoms or one or more alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano, C₁-C₇-alkoxycarbonyl, C₁-C₇-alkylsulfonyl, amino, or C₁-C₇-dialkylamino groups; or a heteroaryl or substituted heteroaryl group derived from imidazole, pyrrole, thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4- or 1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole, pyrazine, pyridazine, pyrimidine, pyridine, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzopyran, indole, isoindole, indazole or quinoline and the heteroaryl substituents comprise one or more C₁-C₆-alkyl, hydroxyl or phenyl groups
 11. The compound of claim 1 wherein G is a monovalent radical of Formula VI_(g),

b_(g) is 0, 1, 2, or 3; e_(g) is 0 or 1; R¹⁸ _(l) is a hydrogen atom, a normal or branched C₁-C₈-alkyl group, a halogen substituted normal or branched C₁-C ₈-alkyl group, a C₃-C₈-cycloalkyl group, a C₃-C₈-cycloalkyl-C ₁-C₄-alkyl group, an aryl group or a substituted aryl group wherein the aryl substituents comprise one or more halogen atoms or one or more alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano, C₁-C₇-alkoxycarbonyl, C₁-C₇-alkylsulfonyl, amino, or C₁-C₇-dialkylamino groups.
 12. The compound of claim 1 wherein G is a monovalent radical of Formula VII_(g),

d_(g) is 0, 1, 2, or 3; eg is 0 or 1; R¹⁹ _(l) and R²⁰ _(l) are, independently, a hydrogen atom, a normal or branched C₁-C₈-alkyl group, a halogen-substituted C₁-C₈-alkyl group, a C₃-C₈-cycloalkyl group, a C₃-C ₈-cycloalkyl-C₁-C₄-alkyl group, an aryl group or a substituted aryl group wherein the aryl substituents comprise one or more halogen atoms or one or more alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano, C₁-C₇-alkoxycarbonyl, C₁-C₇-alkylsulfonyl, amino, or C₁-C₇-dialkylamino groups; a heteroaryl or substituted heteroaryl group derived from imidazole, pyrrole, thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4- or 1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole, pyrazine, pyridazine, pyrimidine, pyridine, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzopyran, indole, isoindole, indazole or quinoline and the heteroaryl substituents comprise one or more C₁-C₆-alkyl, hydroxyl or phenyl groups; or R¹⁹ _(l), R²⁰ _(l) and the nitrogen atom form a ring system comprising 6 or fewer carbon atoms.
 13. The compound of claim 1 wherein G is an alkylene sulfoxide or an alkylene sulfone of Formula VIII_(g),

g_(g) is 1 or 2, h_(g) is 1 or 2, and R²¹ _(l) is a methyl, trifluoromethyl, ethyl or phenyl group.
 14. A compound of the formula A-B-D-E-F-G wherein A is N,N-dimethylvalyl, B is tertiary-leucyl, D is N-methylvalyl, E is prolyl, F is an aminobenzoic acid residue or an aminocycloalkanecarboxylic acid residue and C is a monovalent radical.
 15. A compound of the formula A-B-D-E-F-G wherein A is N,N-dimethylvalyl, B is valyl, D is N-methyl-tertiaryleucyl, E is prolyl, F is an aminobenzoic acid residue or an aminocycloalkanecarboxylic acid residue and G is a monovalent radical.
 16. A compound of the formula A-B-D-E-F-G wherein A is N-methyl-d-prolyl, B is valyl, D is N-methylvalyl, E is prolyl, F is an aminobenzoic acid residue or an aminocycloalkanecarboxylic acid residue and G is a monovalent radical.
 17. A compound of the formula A-B-D-E-F-G wherein A is N-methylhomoprolyl, B is valyl, D is N-methylvalyl, E is prolyl, F is an aminobenzoic acid residue or an aminocycloalkanecarboxylic acid residue and G is a monovalent radical.
 18. A compound of the formula Me₂Val-Val-MeVal-Pro-F-G, wherein F is of Formula II_(f) and R_(f) is a hydrogen atom or a methyl group, R¹ _(f) and R² _(f) are each a hydrogen atom, an alkyl group or an alkoxy group, and G is an amino group, an N-substituted amino group, a hydrazido, an alkyl, cycloalkyl, aryl, or alkylaryl, an alkylene ester, an alkylene amide, an alkylene sulfoxide or an alkylene sulfone group or a monovalent radical of the formula —O—R¹³ _(l) or —S—R¹³ _(l), and R¹³ _(l) is an alkyl, aryl or alkylaryl group.
 19. A compound of the formula Me₂Val-Val-MeVal-Pro-F-G, wherein F is of Formula III_(f), R_(f) is a hydrogen atom or a methyl group, a_(f) is 1 or 2, and G is an amino group, an N-substituted amino group, a hydrazido, an alkyl, cycloalkyl, aryl, or alkylaryl, an alkylene ester, an alkylene amide, an alkylene sulfoxide or an alkylene sulfone group or a monovalent radical of the formula —O—R¹³ _(l) or —S—R¹³ _(l), and R¹³ _(l) is an alkyl, aryl or alkylaryl group.
 20. A method for treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 .
 21. The method of claim 45 wherein the mammal is a human. 